Dopamine Agonists and Antagonists in Duodenal Ulcer Disease

8 Dopamine Agonists and Antagonists in Duodenal Ulcer Disease S. S Z A B O Brigham and Women's Hospital and Harvard Medical School, Departments of Pathology, Boston, MA 02115

Downloaded by GEORGETOWN UNIV on October 29, 2014 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.ch008

J. L . N E U M E Y E R Northeastern University, College of Pharmacy and Allied Health Professions, Section of Medicinal Chemistry, Boston, MA 02115

Recent data in our l a b o r a t o r i e s i n d i c a t e d the p o s s i b l e involvement o f c e n t r a l and p e r i p h e r a l dopamine binding s i t e s in the pathogenesis o f duodenal u l c e r a t i o n . Structure a c t i v i t y s t u d i e s with duodenal ulcerogens implicated dopamine as a p u t a t i v e mediator and/or modulator i n duodenal u l c e r a t i o n . Using the cysteamine- or p r o p i o n i t r i l e -induced duodenal u l c e r model in rats, we found that dopamine agonists (e.g., bromocriptine, lergotrile, L-DOPA, apomorphine and its d e r i v a t i v e s ) prevented, while the antagonists (e.g., h a l o p e r i d o l , pimozide) aggravated the experimental duodenal u l c e r s . These drugs also modulated the output o f g a s t r i c acid and pepsin, as well as that o f pancreatic bicarbonate and enzymes. The a d m i n i s t r a t i o n o f duodenal u l c e r o gens to r a t s changed the binding c h a r a c t e r i s t i c s o f [ H]-dopamine in the g a s t r i c and duodenal mucosa and muscularis p r o p r i a , as well as in b r a i n r e g i o n s . Thus, c e r t a i n dopamine agonists e s p e c i a l l y dopaminergic aporphine a l k a l o i d s may represent new agents to prevent or t r e a t duodenal u l c e r d i s e a s e . 3

The neurotransmitter dopamine has c u r r e n t l y found c l i n i c a l a p p l i c a t i o n i n the treatment of c a r d i o v a s c u l a r c o l l a p s e and shock. Treatment with dopamine-related drugs has been l i m i t e d to such b r a i n d i s o r d e r s as Parkinson's d i s e a s e , schizophrenia, and hyperprolactinemias. Accumulating data from animal experiments, however, i n d i c a t e the p o s s i b l e involvement o f dopamine i n other d i s e a s e s and the p o t e n t i a l use o f dopamine agonists or antagonists i n these d i s o r d e r s . Gastrointestinal disturbances ( e s p e c i a l l y duodenal u l c e r disease) seem t o represent such a group o f dopamine-sensitive a l t e r a t i o n s . Duodenal u l c e r i s about four times more prevalent than g a s t r i c u l c e r i n t h i s part o f the world (J_,2). U n t i l r e c e n t l y , however, animal models have been a v a i l a b l e mostly f o r g a s t r i c 0097-6156/8 3/0224-0175$06.00/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

176

DOPAMINE

RECEPTORS

erosions and u l c e r s s i n c e almost any chemical i n t o x i c doses produces n o n - s p e c i f i c , s t r e s s u l c e r s (3.·!)· On the other hand, e a s i l y and r a p i d l y r e p r o d u c i b l e duodenal u l c e r s have not been a v a i l a b l e u n t i l the i n t r o d u c t i o n o f p r o p i o n i t r i l e (5^) and cysteamine (6^) models. These c h e m i c a l l y induced duodenal u l c e r s i n the r a t c l o s e l y resemble the human duodenal u c l e r both f u n c t i o n a l l y and m o r p h o l o g i c a l l y (7-10). Furthermore they serve as good animal models to study the pathogenesis o f duodenal u l c e r a t i o n and to t e s t new a n t i - u l c e r o g e n i c drugs. The pathogenesis o f duodenal u l c e r d i s e a s e i s poorly understood and i t s therapy i s mostly e m p i r i c a l (J_ 2). The therapy f o r u l c e r disease has v i r t u a l l y been l i m i t e d to n e u t r a l i z a t i o n o f g a s t r i c acid by antacids and i n h i b i t i o n o f a c i d s e c r e t i o n by a n t i c h o l i n e r g i c s and histamine H receptor antagonists (J_,JJ_). Yet, there i s no inherent d i s o r d e r or imbalance o f histamine or a c e t y l c h o l i n e i n any form o f duodenal u l c e r d i s e a s e . Besides the questionable "vagal hypertone" only hypergastrinemia (e.g., i n Z o l l i n g e r - E l l i s o n syndrome) i n the m i n o r i t y o f p e p t i c u l c e r has been documented (_1_^2). I t i s g e n e r a l l y accepted that duodenal u l c e r disease i s a p l u r i c a u s a l or m u l t i f a c t o r a l d i s o r d e r where g a s t r i c acid i s only one o f the many things to have gone a s t r a y . How can we then expect to have the b e s t , e t i o l o g i c treatment f o r u l c e r disease when only antacids or a n t i s e c r e t o r y agents are used? Although the presence o f (increased?) acid i n the stomach and duodenum i s probably necessary f o r the development o f u l c e r s , the pathogenesis o f u l c e r disease i s much more complex than a simple chemical n e u t r a l i z a t i o n or depressed s e c r e t i o n o f a c i d . In t h i s review we s h a l l present data from our and other l a b o r a t o r i e s and argue that dopamine has as yet an unrecognized e t i o l o g i c r o l e i n the pathogenesis o f duodenal u l c e r d i s e a s e . Dopamine agonists may have m u l t i p l e s i t e s o f a c t i o n i n t h i s disease (e.g., by a f f e c t i n g not o n l y g a s t r i c acid and pepsin, but a l s o the duodenum i t s e l f , the pancreas, adrenals, and b r a i n ) . Nevertheless, the r o l e o f dopamine agonists i n the treatment o f duodenal u l c e r disease has not been explored. T h i s review presents s t r u c t u r e - a c t i v i t y s t u d i e s with chemical duodenal ulcerogens, pharmacologic modulation with dopamine-related drugs and biochemical s t u d i e s with experimental duodenal u l c e r s . A b r i e f d i s c u s s i o n and overview o f i m p l i c a t i o n s o f these f i n d i n g s w i l l conclude t h i s chapter.


f

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 o f Duodenal Ulcerogens Experimental duodenal u l c e r s u n t i l r e c e n t l y , were not e a s i l y induced i n the most commonly used l a b o r a t o r y animals (e.g., r a t s , mice)(12). The few a v a i l a b l e methods were complex and not widely used. For example, the c h r o n i c d e f i c i e n c y o f pantothenic acid i n c e r t a i n s t r a i n s o f r a t s ( 1 3 ) 24-h sc i n f u s i o n o f secretagogues (e.g., histamine, c a r b a c h o l , pentagastrin) i n fasted r a t s (14), f

In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.


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or l o c a l a p p l i c a t i o n o f a c e t i c a c i d on the duodenum (15) were found to cause duodenal u l c e r but the incidence o f these l e s i o n s was low and v a r i a b l e . In 1972 we found that i n j e c t i o n s o f p r o p i o n i t r i l e (Figure 1) c o n s i s t e n t l y produced s o l i t a r y , o f t e n p e r f o r a t i n g duodenal u l c e r s i n the r a t (5). These l e s i o n s occurred 3-5 mm from the pylorus o f the stomach, mostly - as i n humans - on the a n t e r i o r w a l l o f the duodenum. The u l c e r s developed 24-48 h a f t e r the i n i t i a l a d m i n i s t r a t i o n o f p r o p i o n i t r i l e and f r e q u e n t l y penetrated i n t o the l i v e r or pancreas (5^. Cysteamine (Figure 1) was a l s o found to produce duodenal u l c e r s , as w e l l as a d r e n o c o r t i c a l n e c r o s i s i n r a t s (6,16,17)« The l e s i o n i n the duodenum developed even more r a p i d l y (e.g., p e r f o r a t i o n i n 24 h a f t e r a s i n g l e dose) and more p r e d i c t a b l y than with p r o p i o n i t r i l e . A c e t a n i l i d e was the f i r s t a r y l chemical noted to cause duodenal u l c e r ( J 8 ) . Subsequently, 3,4-toluenediamine (^9) and 3 , 4 - t o l u e n e d i t h i o l (20) were a l s o shown to induce duodenal u l c e r s and o c c a s i o n a l l y adrenal n e c r o s i s in r a t s . The o r i g i n a l f i n d i n g s and r e p o r t s on the duodenal ulcerogenic a c t i o n o f chemicals such as p r o p i o n i t r i l e and cysteamine were independent observations. At the time no common s t r u c t u r a l , chemical, or b i o l o g i c property o f these chemicals was apparent. Subsequently, however, we recognized that the duodenal ulcerogenic property o f these chemicals may be associated with a two-carbon (-C-C- or 2C) group bearing methyl, cyano, s u l f h y d r y l or amino group(s) on one or both ends o f the carbon chain (4,20-22). The length o f the carbon backbone i s an important feature f o r the duodenal ulcerogenic p r o p e r t i e s o f such agents. Thus, we hypothesized that p r o p i o n i t r i l e (Figure 1) might be anomalous and that by prolonging the carbon chain with one carbon ( i . e . , o b t a i n i n g n - b u t y r o n i t r i l e ) or by r e p l a c i n g the amino groups i n 3,4-toluenediamine by t h i o l s , we should have chemicals with p o s s i b l y higher duodenal ulcerogenic potency than the o r i g i n a l compounds. Both o f these p r e d i c t i o n s proved c o r r e c t (20). S t r u c t u r e - a c t i v i t y s t u d i e s a l s o revealed that unsaturated d e r i v a t i v e s (e.g., -C=C or -C-C=C, such as a c r y l o n i t r i l e , and various a l l y l compounds), without exception exerted higher a d r e n o c o r t i c o l y t i c than ulcerogenic a c t i o n s (20-22). A d d i t i o n o f a new methylene group to the carbon chain o f p r o p i o n i t r i l e (CH CH CN), r e s u l t i n g i n n - b u t y r o n i t r i l e (CH CH CH CN), enhanced the ulcerogenic e f f e c t , whereas a d d i t i o n o f a bromine or n i t r i l e group at t h i s s i t e decreased, and an amino group a b o l i s h e d , the ulcerogenic a c t i o n . Thus, the ulcerogenic potency o f these r a d i c a l s may be presented as f o l l o w s : -CH >-CN>-Br>-Cl>-NH -0H (20,21). The summary o f our work on s t r u c t u r e - a c t i v i t y s t u d i e s with 56 a l k y l chemicals i s presented i n Figure 2. Compilations of data with terminal n i t r i l e s , amines and t h i o l s revealed that chains with two or three carbons had the highest duodenal 2

2

2



178

DOPAMINE

RECEPTORS

Dopamine

Catecholamine

Bromocriptine

Dopamine AGONIST

Lergotrile

Dopamine AGONIST

(-) Apomorphine. R=CH

3

Dopamine AGONIST

(-)N-n-Propylnorapomorphine. NPA. R=CH CH CH 2

2

3

(-) 10.11 -Methylenedioxy-N-npropylnoraporphine. M DO-NPA

Cysteamine

Dopamine AGONIST

HS

x C H

Propionitrile

H

n-Butyronitrile

HJC'

C

C

H

2

y 2

^CH N

'CH

N H 2

Potent

-

x

C

N

Weak

-

Duodenal

C

N

Potent

-

ulcerogen

Weak

-

X

,

Î

C

N

ι CH

Haloperidol

'

2

^ C H '

H

iso-Butyronitrile

^CH

s

5

F-^^COCH ^^CH ^CX-^ 2

2

H Pimozide

Figure 1.

-Ο-

CHCH

0

X C H 2

N

* ' C H < vο N

i

*

Dopamine ANTAGONIST Dopamine ANTAGONIST

Structure of dopamine, dopamine-related drugs, and chemical duodenal ulcerogens.



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χ—χ ο—ο

Duodenal

Ulcer Disease

Duodenal ulcer Adrenal necrosis

Number of carbons in alkanes

Figure 2. Duodenal ulcerogenic and adrenocorticolytic activities of terminal nitrites, amino and thiol alkanes. (Repro duced with permission from Ref. 34. Copyright 1980, International Institute of Stress.)


179


180

DOPAMINE

RECEPTORS

ulcerogenic index (Figure 2 ) . The peak o f a d r e n o c o r t i c o l y t i c index suggested a s l i g h t (probably one carbon) " s h i f t " to the r i g h t (Figure 2 ) . Among a r y l chemicals t e s t e d , the duodenal ulcerogenic a c t i v i t y of 3 , 4 - t o l u e n e d i t h i o l was p r e d i c t e d on the b a s i s o f our i n i t i a l s t r u c t u r e - a c t i v i t y a n a l y s i s o f the u l c e r o g e n i c p r o p e r t i e s o f p r o p i o n i t r i l e , cysteamine, and 3,4-toluenediamine (20,21). Indeed, replacement o f amines by t h i o l s i n 3,4-toluenediamine not only preserved the ulcerogenic property, but a l s o s l i g h t l y enhanced potency. On the other hand, enlargement o f the space between the s u b s t i t u e n t s i n p o s i t i o n s 3 and 4 i n toluene or benzoic acid (e.g., to 2,4, o r 2,5, or 2,6, or 3,5) abolished the duodenal ulcerogenic a c t i v i t y . Toluene alone i s not an ulcerogen. However, the a d d i t i o n o f an amino group i n a c e r t a i n p o s i t i o n (e.g., o - t o l u i d i n e and p - t o l u i d i n e ) r e s u l t s i n prominent duodenal ulcerogenic a c t i v i t y ( *0. Nevertheless, b e s i d e s the q u a l i t y and p o s i t i o n o f s u b s t i t u e n t s , other f a c t o r s probably a l s o have a r o l e i n the causation o f experimental duodenal u l c e r s , e.g., the v i c i n a l amino groups i n 1,2-diaminocyclohexane, p y r i d i n e , or pyrimidine f a i l e d to be associated with ulcerogenic p r o p e r t i e s . S u r p r i s i n g l y , 4,5-diaminopyrimidine or 1,3-dicyanobenzene exerted mild to moderate duodenal ulcerogenic actions (4). An i n t e r e s t i n g observation i n our s t r u c t u r e - a c t i v i t y s t u d i e s was that ethylamine, a part o f the histamine molecule, 4-(2-ethylamine)imidazole, known f o r a long time to be a potent stimulator o f g a s t r i c s e c r e t i o n , a l s o produced duodenal u l c e r s i n r a t s (20,22). Furthermore, s t r u c t u r a l s i m i l a r i t i e s also e x i s t between dopamine and histamine H^ receptor antagonists metiamide and c i m e t i d i n e (23,24). The duodenal ulcerogenic a c t i o n o f p r o p i o n i t r i l e and cysteamine was confirmed and extended by s e v e r a l authors (7\_8, 25-32). The model, e s p e c i a l l y the r a p i d l y developing cysteamine-induced duodenal u l c e r , was a c t u a l l y introduced i n several l a b o r a t o r i e s to r o u t i n e l y t e s t drugs f o r a n t i - u l c e r a c t i v i t y (7,8,27,33). The cysteamine model, a simple, f a s t , and inexpensive procedure, became e s p e c i a l l y u s e f u l a f t e r a chronic form o f duodenal u l c e r was developed (9) and s i m i l a r i t i e s between the model and human duodenal u l c e r a t i o n were noted (7-10). The pathogenesis o f these experimental duodenal u l c e r s i s poorly understood. The r o l e o f g a s t r i c a c i d , g a s t r i n , somatostatin and neurotransmitters, delayed g a s t r i c emptying and the e a r l y and l a t e morphologic changes i n the duodenum are e x t e n s i v e l y discussed i n recent reviews and o r i g i n a l papers (4,22,31,34-37). The most r e l e v a n t e x t r a p o l a t i o n from s t r u c t u r e a c t i v i t y s t u d i e s , however, i s the p o s s i b i l i t y o f i d e n t i f y i n g p u t a t i v e endogenous modulators and/or mediators o f duodenal u l c e r d i s e a s e . On the b a s i s o f previous d i s c u s s i o n s we suggested that dopamine might be one such neurotransmitter (36^). Consequently, because o f s i m i l a r i t y between dopamine, chemical duodenal


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ulcerogens, dopamine agonists and a n t a g o n i s t s , we hypothesized that dopamine agonists might prevent while antagonists aggravate the cysteamine- or p r o p i o n i t r i l e - i n d u c e d duodenal u l c e r s (36) (Figure 1 ) . The r e s u l t s o f these and new pharmacologic studies are presented i n the next s e c t i o n .


Pharmacologic Modulation with Dopamine-related

Drugs

These s t u d i e s were also performed on Sprague-Dawley female r a t s which had u n l i m i t e d access to Purina l a b o r a t o r y chow and tap water. The d e t a i l s o f these experiments have been described elsewhere ( 3 6 ) . Pretreatment with propylene g l y c o l (solvent f o r bromocriptine) had no e f f e c t on the development o f acute duodenal u l c e r s produced by cysteamine, the dose o f which was chosen to exert submaximal u l c e r o g e n i c e f f e c t i n order to detect other preventing and aggravating a c t i o n s among dopamine-related drugs (Figures 3,4). On the other hand, pretreatment with e i t h e r bromocriptine or l e r g o t r i l e showed a dose- and time-dependent a n t i - u l c e r o g e n i c a c t i o n ( F i g u r e s 3,4). In f a c t , 5 mg o f bromocriptine or l e r g o t r i l e given once d a i l y f o r 4 days was s i g n i f i c a n t l y more e f f e c t i v e than a s i n g l e dose administered 30 min p r i o r to cysteamine, and 21-day pretreatment was s i g n i f i c a n t l y b e t t e r than the 4-day course. M o r t a l i t y i n the cysteamine model was abolished a f t e r prolonged treatment with these ergot a l k a l o i d s . On the other hand, pretreatment with e i t h e r h a l o p e r i d o l or pimozide aggravated both the duodenal u l c e r index and the m o r t a l i t y a f t e r cysteamine a d m i n i s t r a t i o n ( F i g u r e 4) ( 3 6 ) . Also i n the cysteamine duodenal u l c e r model, apomorphine and L-DOPA exerted an a n t i - u l c e r o g e n i c a c t i o n i n a much narrower dose range than the ergots ( 3 6 ) . The a c t i o n s o f these drugs are not s p e c i f i c to cysteamine since the i n t e n s i t y o f p r o p i o n i t r i l e - i n d u c e d acute duodenal u l c e r s was a l s o s i g n i f i c a n t l y diminished a f t e r pretreatment with bromocriptine or l e r g o t r i l e (Table I ) . To gain i n s i g h t i n t o the mechanisms o f these a n t i ulcerogenic a c t i o n s o f dopamine a g o n i s t s , experiments were designed to measure the s e c r e t i o n s o f a c i d and pepsin from the stomach, bicarbonate from the pancreas and duodenum, as w e l l as the a c t i v i t y o f p a n c r e a t i c enzymes t r y p s i n and amylase i n r a t s with c h r o n i c g a s t r i c f i s t u l a ( 3 8 ) . In these s e c r e t o r y s t u d i e s both cysteamine and p r o p i o n i t r i l e increased g a s t r i c a c i d output and decreased duodenal n e u t r a l i z a t i o n o f a c i d (38,39). A s i n g l e dose o f l e r g o t r i l e or bromocriptine s i g n i f i c a n t l y suppressed both the i n i t i a l and the t o t a l a c i d output i n r a t s i n j e c t e d with p r o p i o n i t r i l e (Table I I ) . S u r p r i s i n g l y , pretreatment with ergots for one week (which was associated with b e t t e r a n t i - u l c e r o g e n i c treatment than a s i n g l e dose), s l i g h t l y diminished the p r o p i o n i t r i l e - i n d u c e d i n i t i a l a c i d output, but i t d i d not modify the t o t a l 7 h acid output (Table I I ) . Thus, we seem to be dealing with prominent duodenal a n t i - u l c e r o g e n i c a c t i o n s not


182

DOPAMINE

RECEPTORS

η 100

RG. = Propylene Glycol

80

χ ω "D C 60

α> ()

Η 40

Φ

£

*

I

•σ ο Downloaded by GEORGETOWN UNIV on October 29, 2014 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.ch008

(*)

I

• fc ι

30min

4d

4d

7d

2ld

4d

I mg

5mg

^20

»!

»«

7d

2ld

0.2 mg

Bromocriptine

RG.

Figure 3. Effect of bromocriptine on duodenal ulcer produced by cysteamine in the rat. (Reproduced with permission from Ref. 36. Copyright 1979, The Lancet Ltd.)

100

1 80

Η = Haloperidol Ρ = Pimozide

60

40

—

I

H20

M

•

30min 5mg

4d

4d

7d

21 d

I mg

Lergotrile

7d

21 d

0.2 mg

4d

4d

0.1 mg 0.1 mg

Η

Ρ

Figure 4. Effects of lergotrile, haloperidol, or pimozide on duodenal ulcer pro duced by cysteamine in the rat. (Reproduced with permission from Ref. 36. Copy right 1979, The Lancet Ltd.)


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183

Ulcer Disease

TABLE I . E f f e c t o f Bromocriptine or L e r g o t r i l e on P r o p i o n i t r i l e - i n d u c e d Duodenal U l c e r s i n the Rat

Group

Pretreatment //


1. 2. 3.

None Bromocriptine Lergotrile

Duodenal u l c e r Mortality Incidence Intensity (Pos./Tot.) (Scale:0-3) (%) 16/17 5/9* 6/9

1.2+0.2 0.6+0.3* 0.6+0.2*

88 100 75

// In a d d i t i o n , r a t s o f a l l groups were given p r o p i o n i t r i l e 30 min a f t e r the a d m i n i s t r a t i o n o f dopamine a g o n i s t s . * = p

Dopamine Agonists and Antagonists in Duodenal Ulcer Disease

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