Calcium Antagonists: Classification and Properties - ACS Symposium

1 Calcium

Antagonists:

C l a s s i f i c a t i o n and P r o p e r t i e s

Downloaded by CLARKSON UNIV on October 21, 2013 | http://pubs.acs.org Publication Date: October 14, 1982 | doi: 10.1021/bk-1982-0201.ch001

WINIFRED G. NAYLER University of Melbourne, Department of Medicine, Austin Hospital, Heidelberg, Victoria, Australia Calcium antagonists (slow channel blockers, slow Ca antagonists) are a heterogeneous group of sub stances with widely differing tissue specificities, potency and properties. Some of them exhibit other properties in addition to that of Ca antagonism. In general these drugs can be considered as a sub group of a much larger group of compounds which impede the entry of Ca irrespective of the route of entry. The 'slow channel blockers' can be sub divided on the basis of their differing tissue spec ificities. The purpose of this article is to explore the possibility that a classification which is based on differing tissue specificities may reflect differing modes of action. 2+

2+

2+

Verapamil, nifedipine and diltiazem (Figure 1) belong to a relatively newly recognized group of drugs known collectively as "calcium antagonists", (1) "slow channel inhibitors", (2) or "calcium entry blockers" (3,4). Other substances which are now thought to belong to this group include niludipine, nimodipine, prenylamine, fendiline, caroverine, cinnarizine and perhexeline. The possibility of using these and other closely related sub stances in the management of a variety of cardiovascular dis orders - including infarction, (5.,^, 7) arrhythmias, (8,9) angina, (JL0,_11) hypertension (12) and hypertrophic obstructive cardiomyopathies (13) is now being considered. However the "calcium antagonists" that are currently available for such use differ from one another not only in terms of their chemistry, bio-availability and stability, (1,14) but also in potency, (1,14) tissue specificity and possibly in their precise mode of action (15,16,17). Because no attempt has yet been made to subclassify these drugs, the purpose of this article is to explore the problem of providing a suitable classification. To do this i t is necess ary to briefly discuss the physiological significance of the 0097-615 6/82/0201 -0001 $06.00/0 © 1982 American Chemical Society

In Calcium Regulation by Calcium Antagonists; Rahwan, R., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1982.

2

C A L C I U M R E G U L A T I O N B Y C A L C I U M ANTAGONISTS


Verapamil (mol.wt. 454.59) Compound D-600 (gallopamil, mol.wt. 485.59)

M,C CM,

CM' CM, CH,Ο-Α-C CM, CM, CM, Ν CH, CH,-tfS-OCH, 3°-V O N V-OCM, CH

CH

M,C CM, CM CM, 3 ° 1 ^ Ç CM, CM, CM, Ν CM, CM,

Ç3-NO, JLM

Nifedipine (mol.wt., 346.34)

M,C O O C -/S- C O O C M, HjC-y-CM, 1

M Niludipine (mol.wt. 490.55)

Μ^,Ο-H,C

- M,C - ooc -/as-COO - CM,-CM, - OC/ty MjC-V^CM,

M

Nimodipine (mol.wt. 418.45)

H

J

C

Y H

\ M C O O C

v

J T ^ C O O C M , - C M ,- ο - C M ,

^.jC MjC^iT^CM,

M,C ^ Diltiazem (mol.wt. 414.52)

i

CH.

C M , C H I , N < > HCI Ch

Figure 1.

Structural formulas of some Ca

2+

antagonists and their derivatives.


1.

NAYLER

"slow C a els.

Classification

2 +

and

3

Properties

c u r r e n t " (18) and the a s s o c i a t e d i o n - s e l e c t i v e chann2+

The

Slow Ca

Current

2+ The slow Ca c u r r e n t i n heart muscle. In normal heart muscle e x c i t a t i o n i n v o l v e s the a c t i v a t i o n of two d i s t i n c t inward currents (_19^20) . The f i r s t of these currents i s c a r r i e d by Na+ and i s recorded as the f a s t upstroke of the a c t i o n p o t e n t i a l . The Na ions move across the c e l l membrane through v o l t a g e - a c t i v a t e d "channels" that are h i g h l y , but not t o t a l l y , s e l e c t i v e f o r N a . The second inward current i s c a r r i e d mainly (21,22), but not e x c l u s i v e l y (23), by C a . It i s activated slowly, c o n t r i b u t e s to the p l a t e a u phase of the a c t i o n p o t e n t i a l and i s known as "the slow C a c u r r e n t " . The Ca ions i n v o l v e d pass across the c e l l membrane through channels that are h i g h l y s e l e c t i v e f o r C a . L i k e t h e i r Na"" counterparts, the Ca2+s e l e c t i v e channels are v o l t a g e a c t i v a t e d but t h e i r t h r e s h o l d of a c t i v a t i o n (about-55mV) i s higher than that of the N a channels (-35mV). I t i s p o s s i b l e to envisage these "channels" as being p o r e - l i k e s t r u c t u r e s i n the plasmalemma, each pore having i t s own set of " a c t i v a t i o n " and " i n a c t i v a t i o n " gates. In t h i s analogy v o l t a g e a c t i v a t i o n can be l i k e n e d to the opening of "gates" which are c l o s e d during the r e s t i n g s t a t e (24). Taking t h i s hypothesis one step f u r t h e r i t can be argued that the normal opening and c l o s i n g of these "gates" i n v o l v e s voltage-dependent changes i n the c o n f i g u r a t i o n a l s t a t e of the membrane. T h i s same argument a p p l i e s i r r e s p e c t i v e of whether the i o n - s e l e c t i v e "channels" are "porel i k e " s t r u c t u r e s or a p a r t i c u l a r combination or o r g a n i z a t i o n of the membrane p r o t e o l i p i d s that f a c i l i t a t e s the inward movement of c e r t a i n i o n s . Within t h i s framework drugs which i n t e r a c t with the c e l l membrane may a l t e r the configurâtional s t a t e of the membrane, thereby a l t e r i n g the i o n s e l e c t i v i t y or responsiveness of the "gated" channels and p r o t e o l i p i d complexes.


+

2 +

2 +

2 +

1

+

2+ The

slow Ca

current and e x c i t a t i o n - c o n t r a c t i o n c o u p l i n g .

2+ The slow Ca current accounts f o r the entry i n t o the c y t o s o l of between 5 and 10 ymoles C a / k g heart weight/beat (25). This i s approximately one tenth of the C a needed to a c t i v a t e cont r a c t i o n (26). Probably the Ca ions that enter as the main charge c a r r i e r s f o r the slow current serve as a t r i g g e r f o r the m o b i l i z a t i o n of C a from the i n t r a c e l l u l a r s t o r e s (27,_28). However, s i n c e the magnitude of the mechanical response v a r i e s according to the e x t r a c e l l u l a r c o n c e n t r a t i o n of C a (29) i t i s probably the c u r r e n t - c a r r y i n g Ca ions of the slow inward c u r r e n t which d e t e r mine the amount of C a m o b i l i z e d f o r i n t e r a c t i o n with the myofilaments. In other words, the C a - i n d u c e d " t r i g g e r " r e l e a s e of Ca from the i n t r a c e l l u l a r storage s i t e s simply provides an 2+

2 +

2 +

2 +

2 +

2+

2 +


C A L C I U M R E G U L A T I O N BY

4

CALCIUM

ANTAGONISTS

i n t e r n a l a m p l i f i c a t i o n f a c t o r . S k e l e t a l muscle d i f f e r s from c a r d i a c muscle i n that i t m o b i l i z e s a l l the C a i t requires for e x c i t a t i o n - c o n t r a c t i o n coupling d i r e c t l y from i t s own i n t r a c e l l u l a r stores. 2 +

2+


The slow Ca tissues.

current i n smooth muscle, nodal and

conducting

2+ The occurrence of "Ca - s e l e c t i v e " , voltage a c t i v a t e d "channels" i s not l i m i t e d to the myocardium. They occur i n most smooth muscle c e l l s - i n c l u d i n g those i n the coronary, c e r e b r a l and p e r i p h e r a l v a s c u l a t u r e (30). The normal a c t i v i t y of pacemaker, nodal and conducting t i s s u e s (31) i s a l s o l a r g e l y dependent upon them. Because of t h e i r widespread d i s t r i b u t i o n i t follows that substances which a f f e c t the f u n c t i o n i n g of these channels w i l l have a profound e f f e c t on the c i r c u l a t i o n . By c o n t r a s t , s k e l e t a l muscle i s r e l a t i v e l y unaffected (32). 2+ S p e c i f i c i t y of slow channels f o r Ca 2+ Although Ca i s the main current c a r r y i n g i o n f o r the slow inward current part of the current i s c a r r i e d by N a (23). Certain divalent cations, including B a and S r , can s u b s t i t u t e for C a as the main charge c a r r i e r (33). Others, i n c l u d i n g N i , C o , and M n are i n h i b i t o r y (34). 2+ The I d e n t i f i c a t i o n of Ca -antagonists Techniques which are c u r r e n t l y being used to i d e n t i f y substances that a l t e r slow channel transport i n v o l v e measurements of the height and d u r a t i o n of the a c t i o n p o t e n t i a l , monitoring the r a t e of uptake of r a d i o a c t i v e l y l a b e l l e d C a , and e l e c t r o p h y s i o l o g i c a l techniques that i n v o l v e suppression of the f a s t N a current. Use of these techniques i s based on the t a c i t assumpt i o n that the drugs we are d e a l i n g with act only on the slow channels. Later i n t h i s chapter we w i l l summarize the data which suggests that such an assumption may no longer be j u s t i f i e d . For the moment, however, i t i s p e r t i n e n t to work w i t h i n t h i s framework. +

2 +

2 +

2 +

2 +

2 +

2 +

+

(a) Height and

d u r a t i o n of the a c t i o n p o t e n t i a l .

To i l l u s t r a t e the use of changes i n the c o n f i g u r a t i o n of the a c t i o n p o t e n t i a l to e s t a b l i s h the presence or absence of "Ca antagonism" we w i l l concentrate on the c a r d i a c a c t i o n potential. The currents which c o n t r i b u t e to the height and d u r a t i o n of the c a r d i a c a c t i o n p o t e n t i a l are complex (20). In a d d i t i o n to the inward c u r r e n t s already r e f e r r e d to there are at l e a s t two and p o s s i b l y three outward (35) K"*" c u r r e n t s . A c c o r d i n g l y , unless a substance i s s p e c i f i c f o r only the inward Ca"*" current s t u d i e s 2 +

2


1.

NAYLER

Classification

and

5

Properties

which depend upon the monitoring of changes i n the height and duration of the a c t i o n p o t e n t i a l are not p a r t i c u l a r l y h e l p f u l i n i d e n t i f y i n g e i t h e r i n h i b i t o r s or a c t i v a t o r s of slow channel t r a n s port. T h i s d i f f i c u l t y i s f u r t h e r compounded by the f a c t that the subsarcolemmal concentration of C a i n f l u e n c e s the outward K c u r r e n t s , (35) and hence the shape and d u r a t i o n of the a c t i o n potential. 2 +

+

(b) I s o t o p i c Techniques 2+ The use of r a d i o a c t i v e l y l a b e l l e d Ca to monitor changes i n the magnitude and duration of the slow C a current i s a l s o d i f f i c u l t , p a r t l y because of the small amounts of C a that are i n v o l v e d . When considered on a beat to beat b a s i s the C a that enters heart muscle c e l l s by way of the slow C a current represents l e s s than 2 percent of the t o t a l t i s s u e C a and i f , as seems probable, t h i s small component i s r a p i d l y r e c y c l e d to the e x t e r i o r i t s accurate d e t e c t i o n during the time course of the a c t i o n p o t e n t i a l presents s u b s t a n t i a l t e c h n i c a l d i f f i c u l t i e s . There i s , however, another and more s e r i o u s o b j e c t i o n to the use of l a b e l l e d C a f o r t h i s purpose. T h i s d i f f i c u l t y centres around the f a c t that Ca2+ can enter the myocardium and other e x c i t a b l e c e l l s through s e v e r a l d i f f e r e n t routes - i n c l u d i n g i n exchange f o r Na , by passive d i f f u s i o n , and (Figure 2) i n exchange f o r K . Consequently even i f the uptake of r a d i o a c t i v e l y l a b e l l e d Ca + i s reduced there can be no c e r t a i n t y that the p a r t i c u l a r route of entry that i s being a f f e c t e d i s "the slow channels". 2 +


2 +

2 +

2 +

2 +

2 +

+

+

2

(c) E l e c t r o p h y s i o l o g i c a l techniques These i n v o l v e the use of techniques to suppress the f a s t inward N a current. E i t h e r a voltage can be a p p l i e d so that the transmembrane p o t e n t i a l d i f f e r e n c e i s clamped above the l e v e l a t which the N a current i s a c t i v a t e d . (36) or t e t r o d o t o x i n (37) which s p e c i f i c a l l y i n h i b i t s the Na current, can be added, or the membrane can be d e p o l a r i z e d by r a i s i n g the e x t e r n a l K (38,39). Under each of these c o n d i t i o n s the slow inward current can be a c t i v a t e d by adding aminophylline or i s o p r o t e r e n o l , (39) and by e l e c t r i c a l stimulation. +

+

+

Substances That A l t e r Slow Channel

Transport

T h e o r e t i c a l l y , substances or i n t e r v e n t i o n s that a l t e r slow channel transport may do so i n a v a r i e t y of ways:(a) they may a l t e r the amount of C a which i s a v a i l a b l e to a c t as the charge c a r r i e r ; (b) they may, by i n t e r a c t i n g with the c e l l s u r f a c e , evoke a configurât i o n a l change which e i t h e r f a c i l i t a t e s or impedes the approach of C a to the channels; a l t e r n a t i v e l y (c) the configurâtional change i n the membrane may induce a 2 +

2 +


6

C A L C I U M REGULATION

BY

CALCIUM

ANTAGONISTS

change i n the Ca^ - c a r r y i n g c a p a c i t y of each channel; or (d) the number of channels that are o p e r a t i v e at any given time may be a f f e c t e d . T h i s could be achieved by a l t e r i n g the t h r e s h o l d of a c t i v a t i o n , changing the k i n e t i c s of channel a c t i v a t i o n and/or recovery, by f a c i l i t a t i n g the formation of "de novo" channels or by a c t i v a t i n g " s l e e p i n g " channels.


A c t i v a t o r s of slow channel t r a n s p o r t . The catecholamines, i n c l u d i n g norepinephrine, epinephrine and i s o p r o t e r e n o l augment the slow Ca current (39,40). They do t h i s by i n c r e a s i n g the number of channels that are a c t i v a t e d at a given v o l t a g e , without a f f e c t i n g the r a t e of channel a c t i v a t i o n or d e a c t i v a t i o n (40). C y c l i c AMP has the same e f f e c t (41). T h i s a b i l i t y of the catecholamines to r e c r u i t new channels may i n d i c a t e the e x i s t e n c e of a heterogenous p o p u l a t i o n of v o l t a g e - a c t i v a t e d channels, one p o p u l a t i o n being under c y c l i c AMP c o n t r o l . Altern a t i v e l y there may be s e v e r a l d i f f e r e n t s t a t e s of a c t i v a t i o n f o r each channel. I r r e s p e c t i v e of which, i f e i t h e r , of these a l t e r n a t i v e s i s c o r r e c t , i t f o l l o w s that the amount of slow channel a c t i v i t y that i s a v a i l a b l e at any one moment i s i n f l u e n c e d by the c i r c u l a t i n g l e v e l of catecholamine. The recent d i s c o v e r y of c a l c i d u c t i n , a p r o t e i n that appears to be a s s o c i a t e d with the slow channels and which can be phosphorylated by a c y c l i c AMPdependent pathway points towards the p o s s i b i l i t y of heterogeneity w i t h i n the channels. There are other reasons f o r b e l i e v i n g that the channels themselves must be heterogenous. Thus, f o r example, the drugs we are d i s c u s s i n g have no i n h i b i t o r y e f f e c t on the Ca -dependent e x c i t a t i o n - i n d u c e d r e l e a s e of norepinephrine from the sympathetic nerve t e r m i n a l s . T

1

2+

I n h i b i t o r s of slow channel transport. Many substances i n h i b i t slow channel t r a n s p o r t . In a d d i t i o n to the d i v a l e n t c a t i o n s already c i t e d ( M n , Co + and N i + ) , protons, La^+, the metabolic i n h i b i t o r s cyanide and d i n i t r o p h e n o l , are e f f e c t i v e i n h i b i t o r s (24). Other i n h i b i t o r y agents i n c l u d e a c e t y l c h o l i n e , (42) papaverine, (43) p e n t o b a r b i t a l , l i d o f l a z i n e , (44) and adenosine (45) as w e l l as verapamil, n i f e d i p i n e and d i l t i a z e m ( 1 ) . P r e c i s e l y how many of these substances i n t e r f e r e with slow channel transport i s unknown, although i n the case of the metabolic i n h i b i t o r s we can probably account f o r t h e i r e f f e c t i n terms of the energy requirements (24) needed f o r maintaining the configurâtional s t a t e of the c e l l membrane compatible with the maintenance of normal slow channel u l t r a s t r u c t u r e . 2+

2

2

C l a s s i f i c a t i o n of Slow Channel B l o c k e r s (or Antagonists) F l e c k e n s t e i n (1) o r i g i n a l l y c l a s s e d some of the substances l i s t e d i n Table I as "calcium a n t a g o n i s t s " on the b a s i s of two requirements :


NAYLER

Classification


passive transport

and

Properties

Ca /Na exchange 2 +

+

Ca2+ Figure 2.

voltage activated transport

K+

Ca'2+

Ca2+

Schematic representation of possible routes of Ca * myocardial cell. 2

+

T a b l e I : S u b s t a n c e s C l a s s e d a s Ca

entry into a

Antagonists

References Verapamil

1

methoxyverapami1 (D-600)

1

prenylamine

1

nifedipine

1

lidoflazine

44

nimodipine

52,53

diltiazem

1

bepridil

68

caroverine

70

niludipine

53

fendiline

1


8

CALCIUM

R E G U L A T I O N BY C A L C I U M

ANTAGONISTS

(a) the predominant c h a r a c t e r i s t i c of these substances i s t h e i r a b i l i t y to i n h i b i t the slow C a current; and 2+ (b) t h i s i n h i b i t i o n could be overcome by adding Ca 2 +

These c r i t e r i a s t i l l apply. However, the continued u n q u a l i f i e d use of the term "calcium antagonist" r e q u i r e s r e a p p r a i s a l because of i t s l a c k of s p e c i f i c i t y with respect to the s i t e and p r e c i s e mode of drug a c t i o n . Thus "calcium antagonism" can be expressed at a v a r i e t y of s i t e s , i n c l u d i n g the c e l l membrane, the m y o f i b r i l s , the sarcoplasmic r e t i c u l u m and the mitochondria. When used i n t h e r a p e u t i c concentrations, however, the drugs we are d i s c u s s i n g express t h e i r "calcium a n t a g o n i s t i c " p r o p e r t i e s a t only one s i t e - the c e l l membrane. Even a t the c e l l membrane there are other ways i n which substances can i n t e r f e r e with transmembrane C a movements - apart from the entry of C a through the v o l t a g e - a c t i v a t e d "channels". P o s s i b l y , t h e r e f o r e , there i s some merit i n c o n s i d e r i n g drugs of the type shown i n Table I as being a subgroup of a much l a r g e r group of drugs which, f o r want of a b e t t e r term, may be c a l l e d " C a - e n t r y b l o c k e r s " or " C a entry a n t a g o n i s t s " (34). T h i s group of drugs - "the Ca + entry b l o c k e r s " or " C a - e n t r y a n t a g o n i s t s " (Figure 3) would i n c l u d e any drug which impedes the inward movement of C a , i r r e s p e c t i v e of the route of entry. The known routes of C a entry i n t o c a r d i a c and smooth muscle c e l l s i n c l u d e by passive d i f f u s i o n , i n exchange f o r Na , i n exchange f o r K+, and through the v o l t a g e a c t i v a t e d , i o n s e l e c t i v e channels we have been d i s c u s s i n g . As f a r as c a r d i a c and smooth muscle c e l l s are concerned, t h e r e f o r e i t i s p o s s i b l e that four d i f f e r e n t sub groups of Ca -entry b l o c k e r s (or antagonists) w i l l u l t i m a t e l y become a v a i l a b l e . However, the drugs which are c u r r e n t l y a v a i l a b l e are s p e c i f i c only f o r the subgroup that i n v o l v e s the i n f l u x of Ca2+ through the voltage a c t i v a t e d , i o n s e l e c t i v e channels. Since these channels are slowly a c t i v a t e d r e l a t i v e to the channels that s e l e c t i v e l y f a c i l i t a t e the r a p i d i n f l u x of N a during the f a s t upstroke phase of the a c t i o n p o t e n t i a l i t may be more appropriate to r e f e r to these substances as " i n h i b i t o r s of slow channel t r a n s p o r t " . An a l t e r n a t i v e term - " C a channel b l o c k e r " has already appeared i n the l i t e r a t u r e but may be i n a p p r o p r i a t e because the slow channels are not t o t a l l y s e l e c t i v e f o r C a . They a l s o admit some N a and the r e s u l t a n t "slow" Na -dependent current i s blocked by some of the c u r r e n t l y a v a i l a b l e antagonists, i n c l u d i n g verapamil and methoxy verapamil (23). Presumably as new C a entry b l o c k i n g drugs are developed substances that s p e c i f i c a l l y i n h i b i t the i n f l u x of C a through routes of entry other than the slow channels w i l l become a v a i l a b l e . For example, substances that s p e c i f i c a l l y i n h i b i t the entry of C a i n exchange f o r N a or K may be developed. Such substances could be of c l i n i c a l importance because these other routes of C a entry may be i n v o l v e d (43) i n the massive i n f l u x of C a that occurs (46) when flow i s re-introduced to a p r e v i o u s l y ischaemic zone - as may occur, f o r


2 +

2 +

2+

2 +

2

2+

2 +

2 +

+

+

2 +

2

+

+

2 +

2 +

2 +

+

2 +

2 +


+

1.

NAYLER

Classification

and

Properties

9

example, when coronary vasospasm i s r e l i e v e d , a thrombus i s d i s s olved or removed, or r e v a s c u l a r i z a t i o n takes p l a c e . Subclassif ication Substances which i n h i b i t slow channel transport can be conv e n i e n t l y subdivided i n t o two major subgroups, on the b a s i s of t h e i r chemistry. Thus there are the i n o r g a n i c (Co +, Mn +, La3+) and the organic i n h i b i t o r s . The organic i n h i b i t o r s can be f u r t h e r subdivided i n t o three main c l a s s e s , on the b a s i s of t h e i r t i s s u e s p e c i f i c i t y . According to t h i s scheme drugs which predominately a f f e c t slow channel a c t i v i t y i n the myocardium - example v e r a pamil, can be c l a s s e d as having strong C l a s s I a c t i v i t y (47). C l a s s I I could i n c l u d e those drugs which are most e f f e c t i v e i n b l o c k i n g slow channel transport i n v a s c u l a r smooth muscle. N i f e d i p i n e would provide the prototype f o r t h i s subgroup (47). C l a s s I I I would i n c l u d e those substances which are most potent i n b l o c k i n g slow channel transport i n pacemaker, nodal and conducting t i s s u e s . Verapamil, t h e r e f o r e would have strong C l a s s I I I a c t i v i t y , (8) whereas n i f e d i p i n e would have only weak C l a s s I I I a c t i v i t y (48,49). D i l t i a z e m (11) e x h i b i t s strong C l a s s I I a c t i v i t y (50,51). These r e l a t i v e a c t i v i t i e s are summarized i n Table I I . Working from such a c l a s s i f i c a t i o n i t i s r e l a t i v e l y easy to d e t e r mine which p a r t i c u l a r slow channel b l o c k e r should be s e l e c t e d f o r use i n a p a r t i c u l a r s i t u a t i o n . For example, because of i t s strong C l a s s I I I a c t i v i t y verapamil i s the drug of choice i f i t i s the Ca + currents i n nodal, pacemaker or conducting t i s s u e s that are to be suppressed. On the other hand n i f e d i p i n e may be the drug of choice f o r r e l i e v i n g coronary a r t e r y spasm - an a c t i v i t y which would r e f l e c t i t s strong C l a s s II a c t i v i t y . C l a s s I I drugs can be f u r t h e r subdivided i n t o at l e a s t three subgroups (Figure 3). For example the e f f e c t of d i l t i a z e m on the slow channels i s more marked i n the smooth muscle c e l l s of the coronary (51) than the p e r i p h e r a l v a s c u l a t u r e . Nimodipine (52) a c t s p r e f e r e n t i a l l y on slow channel transport i n the c e r e b r a l v e s s e l s , where i t blocks thromboxane-induced c o n t r a c t i o n s (53). By c o n t r a s t , l i d o f l a z i n e i s more potent i n the periphery. Even w i t h i n the coronary c i r c u l a t i o n there i s room f o r f u r t h e r subc l a s s i f i c a t i o n according to whether i t i s the small or l a r g e v e s s e l s (Figure 3) that are being a f f e c t e d (45). For example, adenosine, which i s a r e l a t i v e l y weak C a entry b l o c k e r , a c t s on smooth muscle c e l l s i n the small coronary a r t e r i e s , whereas d i l t iazem and n i f e d i p i n e act p r e f e r e n t i a l l y on the l a r g e v e s s e l s . Why the v a r i o u s organic i n h i b i t o r s d i f f e r with respect to t h e i r p r e f e r r e d s i t e of a c t i o n i s unknown. Is i t because of t h e i r d i f f e r e n t chemical s t r u c t u r e ? Or are the slow C a channe l s themselves t i s s u e s p e c i f i c ? Some substances - eg. pentobarbitone and adenosine, which are r e l a t i v e l y weak slow channel b l o c k e r s do not d i s p l a y t i s s u e s p e c i f i c i t y with respect to t h e i r C a 2 antagonism. Indeed i n these substances i t i s questionable


2

2

2

2 +

2 +

+


C A L C I U M REGULATION B Y C A L C I U M ANTAGONISTS

Ca

Entry Blockers /Antagonists

2 +

Ca /Na Exchange


2 +

Passive Transport

+

Slow Ca : K Channel Exchange Transport 2 +

Inorganic

Class I myocardium

Organic

/ κ II

/ /

S

Table I I :

S

conducting + nodal tissue

ii iii coronary cerebral

small vessels Figure 3.

III

vasculature ^ / J \ ^ /

i peripheral

+

large vessels

Proposed subdivision of Ca *-entry blocking drugs. 2

S u b d i v i s i o n of Slow Channel I n h i b i t o r s

Class

Slow Channel I n h i b i t o r Verapamil

Nifedipine

Diltiazem

Lidoflazine

I

strong

weak

weak

absent

II

weak

strong

strong

strong

III

strong

absent

weak

absent


1.

NAYLER

Classification

and

11

Properties

whether, because of t h e i r n o n - s p e c i f i c i t y , these substances be c l a s s i f i e d as slow channel b l o c k e r s .

should

S i t e and Mode of A c t i o n . In the c l a s s i f i c a t i o n shown i n F i g u r e 3 the organic and i n o r g a n i c i n h i b i t o r s of slow channel transport have been grouped together as subgroups of a common type of C a entry b l o c k e r . T h i s does not mean that they have a common s i t e of a c t i o n . For i n s t a n c e , the i n o r g a n i c i n h i b i t o r s - M n , N i a n d Co2+ - act at the outer surface of the c e l l membrane, where they compete with Ca f o r b i n d i n g s i t e s (34,54). By c o n t r a s t the organic i n h i b i t o r s - eg. verapamil, D-600 appear to act at the c y t o s o l i c surface (55,56). Even the organic i n h i b i t o r s d i f f e r i n t h e i r p r e c i s e mode of a c t i o n . For example, n i f e d i p i n e (46) reduces the number of channels that are o p e r a t i o n a l at a given time without a l t e r i n g the k i n e t i c s of channel a c t i v a t i o n or i n a c t i v a t i o n , whereas verapamil (17) a l t e r s the k i n e t i c s of channel r e a c t i v a t i o n so that recovery i s delayed a f t e r a p r i o r p e r i o d of a c t i v i t y . P o s s i b l y t h i s e f f e c t of verapamil i s a s s o c i a t e d with i t s a b i l i t y to d i s p l a c e Ca + from s u p e r f i c i a l l y l o c a t e d b i n d i n g s i t e s (47). T h e o r e t i c a l l y i t should be p o s s i b l e to c l a s s i f y the slow channel b l o c k e r s according to whether or not they a f f e c t the k i n e t i c s of slow channel t r a n s p o r t . In t h i s way we could r e a d i l y separate the n i f e d i p i n e type of drugs from those that are more l i k e verapamil. A l t e r n a t i v e l y can these drugs be subgrouped according to t h e i r chemistry? T h i s p o s s i b i l i t y seems to be remote. Thus d i l t i a z e m i s a benzothiazepine d e r i v a t i v e (Figure 1\ n i f e d i p i n e i s derived from d i h y d r o p y r i d i n e w h i l s t verapamil has some s t r u c t u r a l features i n common with papaverine. S t r u c t u r e a c t i v i t y r e l a t i o n s h i p s are a v a i l a b l e f o r verapamil and n i f e d i p i n e but not, as y e t , f o r d i l t i a z e m . The a c t i v i t y of verapamil as a slow channel i n h i b i t o r depends upon the presence of the two benzene r i n g s and the t e r t i a r y amino n i t r o g e n . Loss of the t e r t i a r y amino n i t r o g e n - as occurs, f o r example, upon q u a r t e r n i z a t i o n , r e s u l t s i n a t o t a l l o s s of a c t i v i t y , w h i l s t s u b s t i t u t i o n s w i t h i n the benzene r i n g s r e s u l t i n a decreased potency. There are s e v e r a l ways of i n t e r p r e t i n g t h i s data. The t e r t i a r y amino n i t r o g e n may be a c t i n g as an e s s e n t i a l "spacer u n i t " , ensuring that the d i s t a n c e between the two aromatic r i n g s i s optimal f o r " r e c e p t o r " occupancy. A l t e r n a t i v e l y permanent i o n i z a t i o n of the n i t r o g e n , as occurs upon q u a r t e r n i z a t i o n , may r e s u l t i n the molecule being unable to penetrate i n t o the membrane. Now i f , as seems l i k e l y , the binding s i t e f o r verapamil i s l o c a t e d at or near the c y t o s o l i c surface of the membrane permanent i o n i z a t i o n could prevent the molecule from reaching i t s b i n d i n g s i t e , thus rendering i t i n a c t i v e . L i k e verapamil, n i f e d i p i n e contains two aromatic r i n g s (Figure 1), but t h i s seems to be the only property shared by these 2 +

2+

2 +


2 +

2


12

C A L C I U M REGULATION

BY

CALCIUM

ANTAGONISTS

two molecules. In the case of n i f e d i p i n e s u b s t i t u t i o n s at the e s t e r p o s i t i o n of the N - h e t e r o c y c l i c r i n g that i n c r e a s e i t s l i p i d s o l u b i l i t y decrease i t s potency as a slow channel i n h i b i t o r . A low l i p i d s o l u b i l i t y , t h e r e f o r e , must be of some importance. In a d d i t i o n , and although the presence of the NO2 group at the ortho p o s i t i o n i s not e s s e n t i a l , s u b s t i t u t i o n s at the ortho, meta or para p o s i t i o n s of the benzene r i n g r e s u l t i n a decreased a c t i v i t y , p a r t i c u l a r l y i f e l e c t r o n donating or e l e c t r o n withdrawing r a d i c l e s are added, or i f long s i d e arms are introduced. I t seems l i k e l y , t h e r e f o r e , that so f a r as n i f e d i p i n e i s concerned low l i p i d s o l u b i l i t y and i t s s t e r i c c o n f i g u r a t i o n are both important. 2+


The heterogeneity of the Ca

antagonists. 2+

We have a l r e a d y mentioned the p o s s i b i l i t y of the Ca channels being heterogeneous. There i s i n c r e a s i n g evidence that the heterogeneity of the slow channel b l o c k e r s may extend beyond t h e i r chemistry to t h e i r p r e c i s e mode of a c t i o n . Thus w h i l s t F l e c k e n s t e i n ' s o r i g i n a l r e c o g n i t i o n of these compounds was based on t h e i r a b i l i t y to i n h i b i t slow channel transport i n the myocardium the potency of the v a s o d i l a t o r a c t i v i t y which some of these substances exert may i n v o l v e more than slow channel i n h i bition. Indeed i t i s always p e r t i n e n t to remember that the i n h i b i t o r y e f f e c t of these substances on membrane a c t i v i t y i n smooth muscle c e l l s has always r e l i e d upon the presence of an abnormal e x t r a c e l l u l a r i o n i c environment - u s u a l l y a r a i s e d K . Data i s beginning to accumulate now which i n d i c a t e s that some of these substances - i n c l u d i n g c i n n a r i z i n e , f l u n a r i z i n e , f e n d i l i n e (57), and f e l o d i p i n e (58) may i n t e r a c t with calmodulin to reduce i t s Ca binding a c t i v i t y . Since the i n t e r a c t i o n of the calmodulin -Ca complex with myosin l i g h t chain kinase p l a y s an important r o l e i n determining the c o n t r a c t i l e s t a t e of smooth muscle c e l l s , t h i s i n t r a c e l l u l a r a c t i o n may account, i n part at l e a s t , f o r the greater s e n s i t i v i t y which some of these drugs e x h i b i t f o r smooth muscle c e l l s - that i s these h i g h l y potent v a s o d i l a t o r s may i n t e r act with the C a - c a l m o d u l i n complex as w e l l as i n h i b i t i n g slow channel t r a n s p o r t . T h i s i s an i n t r i g u i n g p o s s i b i l i t y and i t may provide the b a s i s f o r the d i v i s i o n of these substances as shown i n F i g u r e 3. Thus C l a s s I I compounds could be those which act predominately w i t h i n the c e l l , whereas C l a s s I compounds could i n c l u d e those which act predominately on the v o l t a g e a c t i v a t e d slow channels. An i n t r a c e l l u l a r s i t e of a c t i o n need not be l i m i ted to an e f f e c t on the C a - b i n d i n g a c t i v i t y of calmodulin. Thus there i s some evidence to support the p o s s i b i l i t y that d i l t i a z e m which, because of i t s powerful coronary v a s o d i l a t o r a c t i v i t y (59) would be i n c l u d e d i n the C l a s s I I s u b d i v i s i o n of the slow channel b l o c k e r s , i n h i b i t s the r e l e a s e of Ca + from i n t r a c e l l u l a r storage s i t e s i n smooth muscle c e l l s (60). How then can we account f o r the C l a s s I I I (Figure 3) compounds? To do t h i s we may have to take i n t o account yet another +

2 +

2 +

2+

2 +

2


1.

NAYLER

Classification

and

13

Properties

property of these compounds - that i s the a b i l i t y of some of them, i n c l u d i n g verapamil and d i l t i a z e m (59) to i n t e r f e r e with the f a s t N a channels. This i s an a c t i v i t y which i s expressed at r e l a t i v e l y high dose l e v e l s but which i s absent from those compounds ( n i f e d i p i n e , n i l u d i p i n e and nimodipine) which e x h i b i t strong C l a s s I I but no C l a s s I I I (Figure 3) a c t i v i t y . +

Other P r o p e r t i e s of Slow Channel Blockers Although suppression of the v o l t a g e - a c t i v a t e d inward d i s placement of C a i s undoubtedly the most widely discussed pro perty of the substances l i s t e d i n Table I, some of these drugs e x h i b i t other p r o p e r t i e s that may be of c l i n i c a l relevance. For example verapamil (61,62) and n i f e d i p i n e bind to α receptors i n b r a i n , neuroblastomaglioma h y b r i d (63) and c a r d i a c muscle c e l l s (64). Verapamil and methoxyverapamil a l s o bind f a i r l y t i g h t l y to muscarinic receptors (65). Verapamil and D-600 have an i n h i b i t o r y e f f e c t on N a and conductance, (23,63) an e f f e c t which apparently i s not shared by n i f e d i p i n e . D i l t i a z e m slows the r e l e a s e of C a from smooth muscle sarcoplasmic r e t i c u l u m (66). As f a r as the c i r c u l a t i o n i s concerned, however, these other p r o p e r t i e s of the slow channel b l o c k e r s are probably i n s i g n i f i c a n t when compared with t h e i r i n h i b i t o r y e f f e c t on slow channel and p o s s i b l y on calmodulin- Ca2+ b i n d i n g a c t i v i t y .


2 +

+

2 +

2+ The I d e n t i f i c a t i o n of Ca

-Antagonist Binding S i t e s

P o s s i b l y , and i n the very near f u t u r e , we may be able to subdivide the C a - e n t r y b l o c k e r s i n terms of t h e i r i n t e r a c t i o n with s p e c i f i c membranes-located b i n d i n g s i t e s . Thus, i n a recent study (67) h i g h l y s p e c i f i c b i n d i n g s i t e s have been i d e n t i f i e d i n r a b b i t c a r d i a c homogenates f o r H ^ - l a b e l l e d n i f e d i p i n e . Other C a entry b l o c k e r s have been found to compete with ^ H - n i f e d i p i n e f o r these b i n d i n g s i t e s , the order of potency being n i f e d i p i n e >> D-600 = verapamil > cinnarizine. Interestingly, diltiazem and perhexeline were found not to i n h i b i t % n i f e d i p i n e b i n d i n g . Thus there i s now good reason f o r b e l i e v i n g that i t i s not only the slow C a channels themselves which are heterogeneous: the drugs which we now b e l i e v e to i n t e r a c t with them are a l s o h e t e r ogeneous not only i n t h e i r chemistry, but a l s o i n t h e i r mode of a c t i o n . As might have been expected substances with C a anta gonist p r o p e r t i e s are now being i s o l a t e d from some of the t r a d i t i o n a l h e r b a l cures - one such i s t a n s h i n o n e , an e f f e c t i v e a n t i a n g i n a l compound that has been i s o l a t e d from the r o o t s of S a l v i a m i l t i o r r h i z a Bunge used as Dan Shen i n t r a d i t i o n a l Chinese medicine (69). 2+

2 +

2 +

2 +

1

1


14

CALCIUM REGULATION BY CALCIUM ANTAGONISTS

Conclusion 2+ The currently available slow channel inhibitors (or Ca antagonists) can be conveniently classed as a subgroup of a large group of compounds which block the entry of Ca into cells. Within this subgroup further subclassification is possible, based on tissue specificity. Whilst such a classification does not explain why these substances differ with respect to their tissue specificity, it provides a useful framework for comparing their different modes of action. Literature Cited 1. Fleckenstein, A. Specific inhibitors and promoters of calcium action in the excitation-contraction coupling of heart muscle. In: Calcium and the Heart, eds. Harris, Ρ and Opie, L. Academic Press, London 1970, 135-188. 2. Katz, A.M.; Reuter, H. Am. J. Cardiol. 1979, 44, 188-190. 3. Nayler, W.G. European Heart J. 1980, 1, 225-237. 4. Nayler, W.G.; Grinwald, P. Fed. Proc. 1981, 40, 2855-2861. 5. Christlieb, I.Y.; Clark, R.E.; Nora, J.D.; Henry, P.D.; Fischer, A.E.; Williamson, J.R.; Sobel, B.E. Am. J. Cardiol 1979, 44, 825-831. 6. Reimer, K.A.; Lowe, J.W.; Jennings, R.B. Circ. 1977, 55, 581-587. 7. Nayler, W.G.; Ferrari, R.; Williams, A. Am. J. Cardiol. 1980, 46, 242-248. 8. Krikler, D.M.; Spurrell, R.A.J. Postgrad. Med. J. 1974, 50, 447-453. 9. Zipes, D.P.; Fischer, J.C. Circ. Res. 1974, 34, 184-192. 10. Andreasen, F.; Boye, E.; Christoffersen, D. Europ. J. Cardiol. 1975, 2, 443-452. 11. Gunther, S.; Green, L.; Muller, J.E.; Mudge, G.H.; Grossmann, W. Am. J. Cardiol. 1979, 44, 793-797. 12. Lewis, G.R.J.; Morley, K.D.; Lewis, B.M.; Bones, P.J. New Zealand Med. J. 1978, 612, 351-354. 13. Rosing D.R.; Kent, K.M.; Maron, B.J.; Condit, J.; Epstein, S.E. Chest. 1980, 78, (Suppl.l) 239-247. 14. Fleckenstein, A. Ann. Rev. Pharmacol. Toxicol. 1977, 17, 149-166. 15. Raschack, M. Arzneim. Forsch. 1976, 26, 1330-1333. 16. Kohlhardt, M.; Fleckenstein, A. Naunyn. Schmiedeberg's Arch. Pharmacol. 1977, 298, 267-272. 17. Kohlhardt, M.; Mnich, Z. J. Mol. Cell. Cardiol. 1978, 10, 1037-1054. 18. Rougier, O.; Vassort, G.; Garnier, D.; Gargouil, Y.M.; Coraboeuf, E. Pfluegers Arch. 1969, 308, 91-110. 19. New, W.; Trautwein, W. Pfluegers Arch. 1972, 334, 1-23. 20. Coraboeuf, E. Am. J. Physiol. 1978, 234, 1101-1116. 21. Beeler, G.W. Jr.; Reuter, H. J. Physiol. (Lond) 1970, 207, 191-209.


2+



1.

NAYLER

Classification

and

Properties

15

22. Reuter, H. Ann. Rev. Physiol. 1979, 41, 413-424. 23. Kass, R.S.; Tsien, R.W. J. Gen. Physiol. 1975, 66, 169-192. 24. Sperelakis, N.; Schneider, J.A. Am. J. Cardiol. 1978, 37, 1079-1085. 25. Langer, G.W. J. Mol. Cell. Cardiol. 1980, 12, 231-240. 26. Solaro, R.J.; Wise, R.M.; Shiner, J.S.; Briggs, F.N. Circ. Res. 1974, 34, 525-530. 27. Nayler, W.G. J. Clin. Orthop. 1966, 46, 157-186. 28. Fabiato, Α.; Fabiato, F. An. New York Acad. Sci. 1978, 307, 491-522. 29. Ringer, S. J. Physiol. 1883, 4, 29-42. 30. Godfraind, T.; Kaba, A. Arch. Int. Pharmacodyn. Ther. 1972, 196, 35-49. 31. Noble, D. Oxford Clarendon Press. 1975. 32. Shine, K.I.; Serena, S.D.; Langer, G.A. Am. J. Physiol. 1971, 221, 1408-1417. 33. Kohlhardt, M.; Haastert, H.P.; Krause, H. Pfluegers Arch. fur die gesamte Physiologic. 1973, 342, 125-136. 34. Kohlhardt, M.; Mnich, Z.; Haap, K. J. Mol. Cell. Cardiol. 1979, 12, 1227-1244. 35. Bassingthwaighte, J.B.; Fry, C.H.; McGuigan, J.A.S. J. Physiol. 1976, 262, 15-37. 36. Beeler, G.W.; Reuter, H. J. Physiol. 1970, 207, 165-190. 37. Shigenobu, K.; Sperelakis, N. J. Mol. Cell. Cardiol. 1971, 3, 271-286. 38. Pappano, A.J. Circ. Res. 1970, 27, 379-390. 39. Schneider, J.Α.; Sperelakis, N. J. Mol. Cell. Cardiol. 1975, 7, 249-273. 40. Reuter, H.; Scholz, H. J. Physiol. 1977, 264, 49-62. 41. Watanabe, A.B.; Besch, H.R. Circ. Res. 1974, 35, 316-324. 42. Ikemoto, Y.; Goto, M. J. Mol. Cell. Cardiol. 1977, 9, 313-326. 43. Schneider, J.Α.; Brooker, G.; Sperelakis, N. J. Mol. Cell. Cardiol. 1975, 7, 867-876. 44. Van Nueten, J.M.; Wellens, D. Arch. Int. Pharm. Ther. 1979, 242, 329-331. 45. Harder, D.R.; Belardinelli, L.; Sperelakis, N.; Rubio, R.; Berne, R.M. Circ. Res. 1979, 44, 177-182. 46. Shen, A.C.; Jennings, R.B. Am. J. Path. 1979, 67, 417-440. 47. Nayler, W.G.; Szeto, J. Cardiovasc. Res. 1972, 6, 120-128. 48. Ebner, F.; Donath, M. Mode of action and efficacy of nifed ipine in 4th International Adalat Symposium. ed. P. Peuch, R. Krebs. Publ. Excerpta Medica. Amsterdam, 1980, 25-34. 49. Rowland, E.; Evans, T.; Krikler, D. Brit. Heart. J. 1979, 42, 124-127. 50. Kusukawa, R.; Kinoshita, M.; Shimoto, Y.; Tomonaga, G.; Hoshina, T. Arzneim. Forsch. 1977, 21, 878-883. 51. Henry, P.D.; Shuchleib, R.; Borda, L.R.; Roberts, R.; Williamson, J.R.; Sobel, B.E. Circ. Res. 1978, 43, 372-380. 52. Towart, R.; Kazda, S. Brit. J. Pharmacol. 1979, 67, 409P.


16

53. 54. 55. 56. 57. 58.


59. 60. 61. 62. 63. 64. 65. 66. 67. 68. 69. 70.

C A L C I U M R E G U L A T I O N BY C A L C I U M

ANTAGONISTS

Towart, R.; Perzborn, E. Europ. J. Pharm. 1981, 69, 213-215. Kohlhardt, M.; Wais, V. J. Mol. Cell. Cardiol. 1979, 11, 917-922. Payet, M.D.; Schanne, O.F.; Ruiz-Ceretti, E.; Demers, J.M. J. Mol. Cell. Cardiol. 1980, 12, 187-200. Payet, M.D.; Schanne, O.F.; Ruiz-Ceretti, E. J. Mol. Cell. Cardiol. 1980, 12, 635-638. Spedding, M. Brit. J. Pharm. 1982, 75, 25P. Bostrom, S.L.; Ljung, B.; Mardh, S.; Forsen, S.; Thulin, E. Nature. 1981, 292, 777-778. Henry, P.D. Amer. J. Cardiol. 1980, 46, 1047-1058. Takenaga, H.; Magaribuchi, T.; Nakajima, H. Japan J. Pharm. 1979, 28, 457-464. Fairhurst, A.S.; Whittaker, M.L.; Ehlert, F.J. Biochem. Pharm. 1980, 29, 155-162. Glossmann, H.; Hornung, R. Mol. Cell. Endrocrinol. 1980, 19, 243-251. Atlas, D.; Adler, M. Proc. Natl. Acad. Sci. 1981, 78, 1237-1241. Nayler, W.G.; Thompson, J.E.; Jarrott, B. J. Mol. Cell. Cardiol. In Press, 1982. Cavey, D.; Vincent, J.P.; Lazdunski, M. FEBS letters. 1977, 84, 110-115. Takenaga, H.; Magaribuchi, T.; Nakajima, H. Japan. J. Pharm. 1979, 28, 457-464. Holk, M.; Thorens, S.; Haeusler, G. European J. Pharm. In press, 1982. Vogel, S.; Crampton, R.; Sperelakis, N. J. Pharm. Exp. Therap. 1979, 210, 378-385. Patmore, L.; Whiting, R.L. Brit. J. Pharm. 1982, 75, 149P. Ikeda, N.; Kodama, I.; Shibata, S.; Kondo, N.; Yamada, K. Cardiovasc. Pharm. 1982, 4, 70-75.

RECEIVED July 14, 1982.


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