Centrally Acting Antihypertensive Agents - ACS Symposium Series

2 Centrally Acting Antihypertensive Agents WOLFGANG H O E F K E

Downloaded by EMORY UNIV on April 1, 2016 | http://pubs.acs.org Publication Date: June 1, 1976 | doi: 10.1021/bk-1976-0027.ch002

Department of Pharmacology, C. H. Boehringer Sohn, Ingelheim, W. Germany

To show how complex it i s t o i n f l u e n c e h i g h b l o o d p r e s s u r e w i t h t h e r a p e u t i c agents some i n f o r m a t i o n on the p h y s i o l o g y o f b l o o d p r e s s u r e r e g u l a t i o n is g i v e n ( F i g . 1 ) . The p r o c e s s o f r e g u l a t i n g b l o o d p r e s s u r e can be compared w i t h a p h y s i c a l c o n t r o l system where intravascular p r e s s u r e i s the c o n t r o l l e d p r o c e s s which has an o u t p u t v a r i a b l e c o n t i n u o u s l y measured by a feedback t r a n s d u c e r - the arterial baroreceptors providing aff e r e n t i n f o r m a t i o n f o r the controlling system in the c e n t r a l nervous system - i n s h o r t "the b l o o d p r e s s u r e r e g u l a t i n g system in the m e d u l l a o b l o n g a t a " . In the controlling system a s e t l e v e l o f b l o o d p r e s s u r e s e r v e s as a s t a n d a r d f o r comparison w i t h the measured i n p u t o f the system, and the d i f f e r e n c e between the two p r o v i d e s a s i g n a l f o r the autonomic e f f e c t o r , which in t u r n inf l u e n c e s the c o n t r o l l e d p r o c e s s . B e s i d e s the arterial baroreceptors, central proj e c t i o n s from o t h e r i n p u t s , f o r example c a r d i a c mechan o - r e c e p t o r s , c h e m o - r e c e p t o r s , pulmonary stretch receptors, and somatic i n p u t s , a r e c a p a b l e o f i n f l u e n c i n g the controlling system and t h e r e b y the autonomic e f f e c tors. There i s a n o t h e r system i n v o l v e d i n b l o o d p r e s s u r e r e g u l a t i o n : the r e n i n - a n g i o t e n s i n - a l d o s t e r o n e system ( F i g . 2 ) . The a r t e r i a l b l o o d p r e s s u r e i n the k i d n e y i n f l u e n c e s i n t r a r e n a l b a r o r e c e p t o r s which t o g e t h e r w i t h the sodium l o a d a t the macula densa l e a d t o r e n i n l i b e r a t i o n , a n g i o t e n s i n f o r m a t i o n and a l d o s t e r o n e s e c r e t i o n , which by i n f l u e n c i n g the sodium b a l a n c e changes the b l o o d volume and i n f l u e n c e s the a r t e r i a l b l o o d pressure. The a n a t o m i c a l s t r u c t u r e s i n v o l v e d i n the m a i n t e nance and r e g u l a t i o n o f the a r t e r i a l b l o o d p r e s s u r e a r e b r i e f l y the f o l l o w i n g ( F i g . 3 ) : 1. the a r t e r i a l w a l l , 2. the a d r e n e r g i c r e c e p t o r s , 3. the p o s t - g a n g l i o n i c 27 Engelhardt; Antihypertensive Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1976.

28

ANTIHYPERTENSIVE AGENTS

OTHER INPUTS

H

OTHER CIRCULATORY

art. blood composition lung inflation somatic etc.

MECHANORECEPTORS cardiac pulmonary

DISTURBANCE HEART AND BLOOD VESSELS

C.N.S. arterial set point

integrative action

AUTONOMIC EFFECTORS

„ intravascular pressures

arterial ARTERIAL BARORECEPTOR Physiological Reviews Circulatory control system ( 1 )


Figure 1.

*Hochdruck* Figure 2.

Renin-angiotensin-aldosterone system ( 2 )

Engelhardt; Antihypertensive Agents ACS Symposium Series; American Chemical Society: Washington, DC, 1976.


2. HOEFKE

Centrally Acting Antihypertensive Agents

29

part of the adrenergic neuron and the sympathetic nerve ending, 4. the sympathetic ganglion and 5. autonomic structures i n the c e n t r a l nervous system. As already mentioned, a l l these structures are linked by one or more c o n t r o l l i n g systems. By influencing one or the other part of these systems the regulation may change in such a way that the blood pressure f a l l s . My lecture p r i m a r i l y deals with substances influencing these auto nomic structures i n the CNS. I should l i k e to t a l k f i r s t about methyldopa (Fig. 4). I t i s well known that a f t e r stimulation of a sympa t h e t i c nerve, noradrenaline i s l i b e r a t e d at the nerve ending. These noradrenaline molecules combine with aadrenoceptors and are then decomposed by catechol-O-methyl-transferase (COMT) or monoamine-oxydase (MAO) or for the most part go back into the nerve ending (reup take) or into the tissues (diffusion) ( f i g . 5). Phenyl alanine and 1-tyrosine which c i r c u l a t e i n blood are precursors of the catecholamines. Tyrosine i s taken up into the nerve ending. With the a i d of tyrosine hydro xylase, 1-dopa i s synthesised and dopamine i s formed by decarboxylation through the action of dopa-decarboxylase. Dopamine i s then converted to noradrenaline through the action of dopamine-B-hydroxylase. The noradrenaline i s stored inside the granules i n combination with ATP ( f i g . 6). When methyldopa was found c l i n i c a l l y to be an antihypertensive agent as reported by OATES, GILLESPIE, UDENFRIEND and SJOERDSMA (3), i t was thought that the blood pressure lowering e f f e c t of methyldopa was due to competitive blocking of dopa-decarboxylase and subse quent i n h i b i t i o n of noradrenaline synthesis. Biochemi cally methyldopa i s converted to a-methylnoradrenaline which replaces noradrenaline as a sympathetic trans mitter substance. The same holds f o r a-methyl-meta-tyrosine and α-methyl-para-tyrosine which biochemically are changed to metaraminol or α-methyl-octopamine. The blood pressure lowering capacity i n man a f t e r intrave nous treatment with α-methyl-meta-tyrosine has been shown by HORWITZ and SJOERDSMA (4). With a-methyl-paratyrosine c l i n i c a l r e s u l t s have been disappointing SJOERDSMA (5)). CARLSSON and LINDQVIST (6) were the f i r s t to indicate that under treatment with methyldopa α-methylnoradrenaline and not noradrenaline i s possibly released from the storage granules. On the basis of s i milar findings DAY and RAND (7) were able to present the theory that stimulation of nerves causes ot-methylnoradrenaline to be released from the storage granules of the sympathetic nerve endings as a f a l s e transmitter substance. This i s based on t h e i r findings that a-methylnoradrenaline i s 2 - 8.5 times less potent than


30



Brain reserpine clonidine methyldopa

Sympathetic Nerve Ending guanethidine reserpine Figure 3.

Sympathetic Ganglion hexamethonium

Anatomical structures involved in circulatory regulation

Methyldopa Figure 4.

Chemical structure of methyldopa

Figure 5. Schematic of nerve ending and effector cell. 1, liberation of nor adrenaline (NA); 2, reuptake; 3, com bining with α-adrenergic receptor; 4, diffusion; 5, degradation of ΝA. MAO = mono amine oxydase, COMT = catechol-O-methyl-transferase.



2.

HOEFKE


31

noradrenaline i n widely d i f f e r i n g t e s t models. The the ory of DAY and RAND had been disputed by several wor kers who have been unable to e s t a b l i s h a l e s s potent b i o l o g i c a l a c t i v i t y of α-methylnoradrenaline, among them PALM et a l . , (8). Experiments done by HENNING and van ZWIETEN (9) with infusions of methyldopa into a pe r i p h e r a l vein or into the vertebral artery of cats r e vealed the f a c t that the lower doses given c e n t r a l l y were more e f f e c t i v e than peripheral administration of larger doses. These, as well as experiments done by INGENITO et a l . (10), indicate a c e n t r a l mode of a c t i o n . At t h i s juncture, a new substance appeared on the scene, namely clonidine ( f i g . 7), of which I s h a l l now give you a more d e t a i l e d p r o f i l e , as I was c l o s e l y i n volved i n the development of t h i s compound (HOEFKE and KOBINGER (11)). Tests c a r r i e d out on dogs exhibited a complex influence of clonidine on the c i r c u l a t i o n as can be seen i n f i g . 8. A transient r i s e i n blood pres sure i s followed by a l a s t i n g f a l l . Increasing the dose causes a more d i s t i n c t r i s e i n blood pressure which might even conceal the hypotensive a c t i v i t y . Hyperten sive and hypotensive actions are accompanied by brady cardia. The n i c t i t a t i n g membrane i s contracted depen ding on the dose. The c a r o t i d sinus r e f l e x produced by clamping both common c a r o t i d a r t e r i e s causes an i n crease i n blood pressure brought about by the decrease in pressure within the region of the c a r o t i d sinus. Clonidine has a dose-dependent i n h i b i t o r y e f f e c t on this reflex. I t can now be seen that an immediate peripheral action on the alpha-receptors of the sympathetic ner vous system cause vasoconstriction, contraction of the n i c t i t a t i n g membrane, increase i n the hematocrit, and mydriasis. Clonidine i s e f f e c t i v e following pretreatment with reserpine which causes discharge of neural noradrenaline and, at the same time, i n h i b i t s periphe r a l e f f e c t s of the sympathetic nervous system. More over, the above-mentioned e f f e c t s can be blocked by a l pha sympatholytic agents such as phentolamine and phenoxy-benzamine. Analysis of the hypotensive as well as bradycardic actions of clonidine exclude to a large ex tent the p o s s i b i l i t y of a peripheral v a s o d i l a t i n g action, peripheral i n h i b i t o r y action on the heart and ganglionic blocking a c t i v i t y (HOEFKE and KOBINGER (11), KOBINGER and HOEFKE (12), KOBINGER and WALLAND (13). The hypotensive action of clonidine could not be explained s a t i s f a c t o r i l y by e f f e c t s on the peripheral c i r c u l a t i o n . Numerous studies therefore considered the p o s s i b i l i t y of an e f f e c t on the c e n t r a l nervous system. Investigations performed on s p i n a l i z e d animals could



( NORADRENALINE

Tyrosinehydroxylase

Dopa-decarboxylase

Dopamine-Πhydroxylase


Figure 6. Schematic of noradrena line synthesis in a sympathetic nerve ending

/r^

CI /NH-CH

CMK N

Figure 7. Chemical struc ture of clonidine

—(

2

ι -hci

N

NH-CH

2

jg/kg

A 3pg/kg

Catapresan 5>jg/kg

Herzfreq.

Monatsblatter fur Augenheilkun.de Figure 9. Blood pressure and heart rate under the influence of clonidine before and after spinalization in a cat. Spinalization was done between the two parts of the figure. Adrenaline (Adr.) and clonidine (Clonidin) were given i.v. (14).

Naunyn-Schmiedeberg's Archives of Pharmacology Figure 10. Blood pressure and heart frequency in an anaesthetized cat with sectioned vagi and pretreatment with atropine (1 mg/kg). Decrease of blood pressure and heart rate in beats/min (S/min) after intracisternal (i.ci.) and intravenous (i.v.) injection of clonidine (15).



2.

HOEFKE


35

extremities. Such an e f f e c t of dopa can be blocked by alpha-adrenolytic agents, for example phenoxybenzamine. Phenoxybenzamine does not influence the synthesis of noradrenaline from dopa; therefore i t must be assumed that phenoxybenzamine blocks adrenergic alpha-receptors in the spinal cord as i t does i n the periphery of the body. The authors used t h i s model f o r t e s t i n g c l o n i d i ne and found that c l o n i d i n e s i m i l a r to dopa causes an i n t e n s i f i c a t i o n of the f l e x o r r e f l e x ; t h i s e f f e c t can be abolished by alpha-adrenolytic agents. The animals were pre-treated with reserpine i n order to exclude the p o s s i b i l i t y of the e f f e c t being brought about by r e lease of noradrenaline. Furthermore, to exclude nor adrenaline synthesis by the precursors, appropriate blocking agents were administered. Further work by SCHMITT and coworkers (20) has supported the hypothesis that adrenergic alpha-recep tors do occur inside the CNS and that they are stimula ted by c l o n i d i n e . By i n t r a c i s t e r n a l administration of the alpha-adrenolytic substance piperoxan the authors succeeded i n abolishing i n cats and dogs the decrease in blood pressure as well as the decrease i n heart rate which had been caused by c l o n i d i n e given i n t r a c i s t e r n a l l y . Whereas the peripheral alpha-receptors stimula ted p h y s i o l o g i c a l l y by noradrenaline cause vasocon s t r i c t i o n , stimulation of the c e n t r a l alpha-receptors causes a decrease i n blood pressure. Noradrenaline can not penetrate the blood-brain b a r r i e r but i f i t i s g i ven i n t r a c i s t e r n a l l y , an action i s exerted on c e n t r a l alpha-receptors, causing a reduction i n blood pressure. Piperoxan again produced an antagonistic e f f e c t . Now l e t us go back to methyldopa. The afore-men tioned experiments by HENNING and van ZWIETEN (21) i n dicated a c e n t r a l mode of action. HEISE and KRONEBERG (22), perfusing part of the t h i r d and the e n t i r e fourth v e n t r i c l e of the brain i n cats with methyldopa, a-methyldopamine and α-methylnoradrenaline were able to show a decrease i n blood pressure. These e f f e c t s were s i g n i f i c a n t l y blocked by pretreatment with yohimbine and to a lesser extent by phentolamine. These experi ments support the concept of blood pressure lowering by an action on c e n t r a l a-adrenoreceptors. The f a c t that the modes of action of c l o n i d i n e and α-methylnoradrenaline are s i m i l a r to the mode of ac t i o n of the p h y s i o l o g i c a l transmitter noradrenaline i n dicates the importance of the r o l e of the l a t t e r i n the c e n t r a l c o n t r o l of blood pressure. I t may be mentioned that 1-dopa too, the precursor of noradrenaline, pene trates the blood-brain b a r r i e r and causes hypotension and bradycardia a f t e r systemic administration, when do-



36


pa-decarboxylase i s i n h i b i t e d e x t r a c e r e b r a l l y by a-hydrazino-a-methyl-β-(3,4-dihydroxyphenyl)-propionic acid (HENNING and RUBENSON (23)). The same action can be seen a f t e r i n t r a v e n t r i c u l a r administration of 1-dopa (BAUM and SHROPSHIRE (24). Experiments by HENNING et a l . (25), s i m i l a r to those of SCHMITT (26) with midc o l l i c u l a r transection of the brain i n rats showed that 1-dopa - a f t e r peripheral dopa-decarboxylase blockade reduced blood pressure i n the same order as i n i n t a c t animals and a f t e r s p i n a l i z a t i o n was no longer a c t i v e . In the integration of cardiovascular regulation i n the so-called "medullary vasomotor centre" two d i f f e r ent areas f o r pressor and depressor a c t i v i t y are i n volved. The main part of the depressor area i s the nu cleus tractus s o l i t a r i i , which i s r i c h i n noradrenaline nerve terminals (DAHLSTROM and FUXE (27)). Ablation of t h i s area leads to hypertension i n rats (DOBA and REIS (28) ), while stimulation of t h i s area causes hypoten sion and bradycardia. The same holds true for microin jections of noradrenaline into t h i s area (de JONG (29) ). This area i s also involved i n the c a r o t i d sinus occlusion r e f l e x , which can be blocked by c l o n i d i n e , as already mentioned. Recently HAEUSLER (30) has shown that the action of c l o n i d i n e bears s i m i l a r i t y to a cen t r a l a c t i v a t i o n of the depressor baroreceptor r e f l e x which was e l i c i t e d by e l e c t r i c a l stimulation of the sinus nerves. An e s s e n t i a l part of the reduction of the blood pressure and bradycardia can be explained by c e n t r a l i n h i b i t i o n of sympathetic tone. However the parasympa t h e t i c system i s also involved i n cardiovascular con t r o l . A decrease i n blood pressure and bradycardia can be produced by c l o n i d i n e even a f t e r i n a c t i v a t i n g the vagus nerve. SCRIABINE and coworkers (31), however, have shown that the e f f e c t of c l o n i d i n e i n anesthetized dogs i s weaker a f t e r i n a c t i v a t i o n of the vagus nerve. ROBSON and KAPLAN (32) also came to the conclusion that clonidine might cause bradycardia by i n t e n s i f i c a t i o n of vagal r e f l e x e s . KOBINGER and WALLAND (33) demonstrated that c l o n i d i n e influences vagal r e f l e x e s as w e l l . In j e c t i o n of vasopressor substances such as noradrenaline and angiotensin cause r e f l e x bradycardia mediated v i a the vagus nerve. Such a bradycardia i s reinforced i f clonidine i s given i n t r a c i s t e r n a l l y , and the r e i n f o r c e ment can be blocked by phentolamine administered i n t r a cisternally. Destruction of c e n t r a l adrenergic neurons by i n t r a v e n t r i c u l a r i n j e c t i o n of 6-hydroxydopamine (6 OHDA) v i r t u a l l y abolished the hypotensive e f f e c t of methyldopa. Adrenergic neurons are probably required to con-



2.

HOEFKE

37


vert methyldopa to α-methylnoradrenaline which i s the active agent. This i s proved by the f a c t that a f t e r pretreatment with the c e n t r a l dopamine-fi-hydroxylase i n h i b i t o r FLA 63, methyldopa shows no blood pressure decreasing properties (HAEUSLER and FINCH (34)). In the case of clonidine, pretreatment with 6 OHDA does not reduce the blood pressure lowering a c t i v i t y according to HAEUSLER and FINCH (34) and WARNKE and HOEFKE (35). This i s contrary to the r e s u l t s obtained by DOLLERY and REID (36) . Also a f t e r pretreatment with reserpine and blocking of noradrenaline synthesis with a-methyl-paratyrosine c l o n i d i n e retains i t s action on the sympathe t i c system (HAEUSLER (37)). The same holds true f o r the i n t e n s i f i c a t i o n of v a g a l l y mediated r e f l e x bradycardia by c l o n i d i n e (KOBINGER and PICHLER (38)). Recent experiments c a r r i e d out by BOLME and cowor kers (39) now r a i s e the question of whether the recep tors involved i n reducing blood pressure are epinephri ne receptors or noradrenaline receptors. These workers found that i n rats small doses of yohimbine and piper oxan blocked the blood pressure lowering e f f e c t of c l o nidine, but did not influence the clonidine-induced i n crease i n f l e x o r r e f l e x a c t i v i t y . This e f f e c t on the r e f l e x mechanism i s possibly mediated by noradrenaline receptors which can be blocked only by higher doses of α-adrenolytic agents. HOKFELT et a l . (40) consider that epinephrine terminals possibly innervate noradrenaline c e l l bodies at the locus coeruleus. MUJIC and van ROSSUM (41) tested several s u b s t i tuted imidazolines used as nasal decongestants. These are s p e c i f i c sympathomimetic agents with a d i r e c t ac t i o n on the α-adrenergic receptors. They proved to be more potent than the n a t u r a l l y - o c c u r r i n g noradrenaline. Clonidine, which was o r i g i n a l l y synthesised as a nasal decongestant, also has strong α-adrenergic a c t i v i t y . Among the substances which were extensively i n v e s t i g a ted by van ROSSUM (41) i s tetrahydrozoline. HUTCHEON et a l . (42) found that i n anaesthetised dogs tetrahy drozoline decreased the blood pressure a f t e r an i n i t i a l increase and simultaneously caused bradycardia. No f a l l in heart rate was observed i n spinal cats i n d i c a t i n g a c e n t r a l mechanism of the pharmacological e f f e c t s . Besides the s i m i l a r b i o l o g i c a l properties of nor adrenaline, c l o n i d i n e and other imadazoline compounds there are also s i m i l a r i t i e s i n the molecular structure ( f i g . 11). I have taken noradrenaline as an example of a substance acting on α-receptors. According to PULMAN et a l . (43), two distances i n the molecule are predomi nant. A distance D from the c a t i o n i c centre N to the centre of the aromatic r i n g equals 5.1 - 5.2 8 and a +


38



+

distance H from the c a t i o n i c centre N to the plane of the aromatic r i n g equals 1.2 - 1.4 8 . In c l o n i d i n e the free r o t a t i o n of the benzene nucleus around the C-N single bond means that two conformational isomers may e x i s t : the planar conformer and the aplanar conformer with the rings perpendicular to each other. The aplanar conformer i s given preference since the planar confor mer i s s t e r i c a l l y hindered by the two c h l o r i n e atoms i n ortho p o s i t i o n s . Using the conformations according to WERMUTH et a l . (44), the distances D= (5.0 - 5.1ft)and H= (1.28 - 1.36 8) can be estimated; these compare well with those of noradrenaline. The 2,6-diethyl analogue (St 91) i s a substance which i s very s i m i l a r to c l o n i d i n e i n i t s chemical structure ( f i g . 12). This compound tested i n spinal rats i s 2.5 times as e f f e c t i v e as c l o n i d i n e i n increa sing blood pressure, but f a i l s to show a decrease i n blood pressure a f t e r intravenous administration to rab b i t s (HOEFKE, KOBINGER and WALLAND (45)). A reduction i n blood pressure, however, can be achieved by giving the compound i n t r a c i s t e r n a l l y i n a dose as low as 0.3 yg/kg ( f i g . 13). The cause f o r t h i s seems to be the i n a b i l i t y of St 91 to penetrate the blood brain b a r r i e r . One p h y s i c a l factor e s s e n t i a l f o r the penetration of b i o l o g i c a l membranes i s l i p o p h i l i c character. When t h i s was tested, the d i s t r i b u t i o n c o e f f i c i e n t (P) between octanol and phosphate buffer at a pH 7.4 was Ρ = 0.06 for St 91 and Ρ = 3.0 f o r c l o n i d i n e . Therefore, d i s t r i bution c o e f f i c i e n t s play an important part i n determi ning the spectrum of pharmacological actions of drugs. The peripheral and c e n t r a l α-adrenergic a c t i v i t i e s of a group of d i - s u b s t i t u t e d c l o n i d i n e analogues with d i f f e r e n t d i s t r i b u t i o n c o e f f i c i e n t s were estimated by i n v e s t i g a t i n g the blood pressure increase i n s p i n a l rats and the bradycardia a f t e r parasympathetic block ade. I t can be seen i n f i g . 14 that the most active agent i n spinal rats i s St 91, which however showed ab s o l u t e l y no a c t i v i t y on heart rate. From these data r e l a t i v e a c t i v i t i e s (clonidine « 1) were calculated and normal logarithms of the product of the α-adrenoceptor a c t i v i t y (hypertension i n spinal rats) times d i s t r i b u t i o n c o e f f i c i e n t were plotted along the x-axis. The normal logarithms of the c e n t r a l cardiodepressor action (bradycardia i n vagotomised rats) were plotted along the y-axis. With the exception of St 91 which showed no c e n t r a l action the c o r r e l a t i o n of these parameters sup ports the hypothesis that a connection e x i s t s between α-adrenergic a c t i v i t y , l i p o i d s o l u b i l i t y and c e n t r a l action (HOEFKE, KOBINGER AND WALLAND (45), f i g . 15). Another physicochemical parameter which was i n v e s t i -



HOEFKE


Journal of Medicinal Chemistry and Clinic Thérapeutique Figure 11. Appropriate structures of clonidine and noradrenaline for interaction with the postulated α-adrenergic receptors (on the basis of data from (43) and (44)).

»-N=(

--NH-CH2

1

"NH—CH

2

'CI

-HCl

St 155

-C H 2

5

>-N=(

,NH—CH

I -HCl 2

^NH—CH

2

' 2 5 C

H

St 91

Figure 12. Chemical structure of clonidine (St 155) and the 2,6diethyl-analog (St 91)



40

St 91

100ug/kg i.v.

χ • S.E. n = 4

30/jg/kg i.v.

x± S.E. n = 8

Blood Pressure mm Hg


120 •

70-J

0,3jjg/kg i.ci.

ι -32

r-16

m-i—ι 0 A 8 16

r— 32

x* S.E. η = 4

ι— 64

126

Figure 13. Mean blood pressure in anaesthetized rabbits (0.75 g/kg urethan i.p. and 30 mg Nembutal i.v.) under the influence of St 91 given either intravenously (i.v.) or intracisternally (i.ci.)


HOEFKE

substance


distribution coefficient

chemical structure

Clonidine

blood pressure E 0 increase in mmHg

octanol / buffer

3 0

heart rate

ED

5 0

decrease in beats/min

0,005

mg/kg

3,0

0,0U mg/kg

006

0,0055 mg/kg

St 93

0,29

0,022 mg/kg

0,0095 mg/kg

Tolonidine

0,11

0,063 mg/kg

0,041

mg/kg

0,15

0,195 mg/kg

0,300

mg/kg

0,27

0,180 mg/kg

0,062

mg/kg

(St 155)

St 91 C

2 5 H

(St 375)


St 600

CH

3 >

.Cl

N

H

St 608

Figure 14. Effects of a group of clonidine derivatives on blood pressure in spinal rats and on heart rate in vagotomized rats. The distribution coefficient was measured with 0.1 m Sôrensen phosphate buffer at a pH of 7.4.

-5,25

-4,50

-3,75

-3,0

-2,25

-1,50

-0,75

0

0,75

1,50

ln(»c-adrenoceptor activity"distribution quotient) blood pressure increase in spinalised rats

Arzneimittelforschung

Figure 15. Relationship between peripheral α-adrenoceptor activity, lipoid solubility, and centrally mediated cardiodepressor activity. Abscissa: natural logarithms of the product of rehtive activity on peripheral α-adrenoceptors as derived from blood pressure decreases in spinal rats multiplied by percentage of distribution between octanol/buffer (Figure 4). Ordinate: natural logarithms of the rela tive CNS activity as derived from bradycardia test in vagotomized rats (45).



42


gated i n connection with the a c c e s s i b i l i t y to c e n t r a l α-receptors i s the pKa. The v a l i d i t y of the c o r r e l a tions between physichochemical parameters and b i o l o g i c a l a c t i v i t y has, however, yet to be investigated with other substances. From a more p r a c t i c a l point of view i t i s possible to test new d e r i v a t i v e s of clonidine i n anaesthetised rabbits to ascertain i f they have a blood pressure lowering capacity or not. With t h i s rather simple method i t was possible to evaluate some r e l a tionships between chemical structure and pharmacologi cal activity. The f i r s t group of compounds to be investigated were substituted phenylimino-imidazolines". The i n t r o duction of one, two or three chlorine atoms shows maxi mal e f f e c t with 2,6-dichloro-substitution ( f i g . 16). The replacement of chlorine by bromine and trifluoromet h y l decreases the hypotensive a c t i v i t y ( f i g . 17). A l t e r n a t i v e l y , switching of the two chlorine atoms to other positions i n the phenyl r i n g also lowers the ac t i v i t y ( f i g . 18). The same applies to bromine s u b s t i t u t i o n ( f i g . 19). The s u b s t i t u t i o n with d i f f e r e n t halogen or a l k y l groups i n the 2- and 6-positions leads to a decrease i n the action on blood pressure ( f i g . 20). The s u b s t i t u t i o n of a l k y l groups i n the 2-, 4- and 6-posi tions shows no c l e a r cut r e l a t i o n s h i p i n s t r u c t u r a l a c t i v i t y . While s u b s t i t u t i o n with a methyl and an ethyl i n the ortho-position shows a low a c t i v i t y , the 2-, 6d i - s u b s t i t u t e d methyl and ethyl compounds are t o t a l l y i n a c t i v e . The 2-methyl-6-ethyl compound, however i s ca pable of lowering the blood pressure. The 2-, 4-, 6t r i s u b s t i t u t e d d e r i v a t i v e s are highly active ( f i g . 21). Here again, the d i s t r i b u t i o n c o e f f i c i e n t i s of impor tance. The mono-substituted and, to a larger extent d i substituted compounds show low values for d i s t r i b u t i o n c o e f f i c i e n t s between octanol and phosphate buffer at pH 7.4 whereas the t r i - s u b s t i t u t e d compounds show high values. Another p o s s i b i l i t y of v a r i a t i o n i n the mole cule i s extension of the bridge between the phenyl r i n g and the imidazoline r i n g . I t can be seen i n f i g . 22 that extension leads to a reduced a c t i v i t y on blood pressure. The expansion of the imidazoline r i n g to a 6-, 7- or 8-membered r i n g as well decreases a c t i v i t y ( f i g . 23). Ring closure reactions of 2-imino-imidazolines lead to annellated b i - and t r i - c y c l i c hetero r i n g s . Here again the blood pressure lowering a c t i v i t y i s r e 5:

A l l the compounds tested were synthesised by Dr. H. STXHLE, Dept. of Pharmaceutical Chemistry, C.H. Boehringer Sohn, Ingelheim, W.-Germany (see also ST&HLE (46) and POOK et a l . (59)).


HOEFKE


blood pressure

CHEMICAL STRUCTURE

decrease m m H g ED

/

C l

NH — C H

U - " - < y

C1

Q-N.< \ \


_ /

C

I

NC1

2 0

m g/kg

2

1,0 0

1

NH — C H

2

NH — CH

2

NH — C H

2

ι

0,0 1

NH — CH2 0.0 9 NH — C H

2

Figure 16. Influence of one, two, or three chlorine atoms in the phenyl ring on blood pressure in anaesthetized rabbits

blood pressure

CHEMICAL STRUCTURE

decrease mmHg ED

/

C 1

NH — C H

2 0

mg/kg

2

0,0 1 0

Cl /

Br

—

C

H

2

CH

NH

CH

2

CH

2

0--< /CF3

H

NH

B r

U - " - < ^ „

N

NH

2

ι . L

1

0.0 U 5

0.0 6 0

Figure 17. Effect of replacement of chlorine in 2,6-position of the phenyl ring by bromine and trifluoromethyl on blood pressure



CHEMICAL STRUCTURE

d-"-< ι /

"

C

W

NH

C 1

C I

C l


Ρ

CH

2

NH

CH

2

NH

CH

2

NH

CH

2

NH

CH

2

0-"-< ι NH

CH

2

C

J

&--

Centrally Acting Antihypertensive Agents - ACS Symposium Series

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