EDITORS' PREFACE
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Τ JL H E I N V I T A T I O N B Y J . L . N E U M E Y E R and the Division of Medicinal Chemistry of the American Chemical Society to organize the symposia "Multiple Categories of Dopamine Receptors" and "Modulation of Dopa mine Receptors" offered us the opportunity to highlight some of the recent advances in the understanding of dopamine receptors and the drugs inter acting with these receptors. Several years ago, John Kebabian presented the "two dopamine receptor hypothesis." This hypothesis is the theme of the first symposium. Similarly, several years ago, Carl Kaiser participated in the discovery of S K & F 38393, a dopaminergic agonist relatively selective for the D - l receptor. The second symposium focuses attention on the development of novel agonists for dopamine receptors and their use as therapeutic agents. Because some of these differentiate between different dopamine receptors, the concept of multiple categories of dopamine receptors is an integral part of the second symposium. The requirement of the American Chemical Society that all material published by the Society be subjected to outside review offered an oppor tunity for us to solicit a second (and sometimes conflicting) opinion about the material presented in these symposia. It cannot be denied that the topic of dopamine receptor(s) remains an area of ongoing investigation, controversy, and disagreement. F o r many questions about dopamine re ceptors, the "final verdict" is not yet in. Indeed, if these symposia have delineated the areas of disagreement, the readers of this volume form the jury. F o r each disagreement or misunderstanding highlighted in this volume, the reader can review the ideas of the different authors and then decide which observations and interpretations are most helpful to their individual endeavors. The editors are grateful to each of the authors of chapters and to those who contributed commentaries on these chapters. We also acknowl edge with gratitude the financial support of Smith Kline & French Laboratories. CARL KAISER
JOHN W. KEBABIAN
Smith Kline & French Laboratories Philadelphia, PA 19101
National Institutes of Health Bethesda, MD 20205
February 1983 ix In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
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PREFACE BY LESLIE L. IVERSEN
THE
CHAPTERS
PRESENTED
HERE
REPRESENT
an interesting state-of-the-
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art reflection of current trends i n research o n d o p a m i n e receptors. D . C a l n e a n d T . A . L a r s e n are p r o b a b l y accurate i n suggesting that " d o p a m i n e has overtaken acetylcholine a n d n o r e p i n e p h r i n e as the most extensively investigated neurotransmitter i n the nervous system." T h e i r a d m i r a b l e survey of present a n d potential c l i n i c a l uses of d o p a m i n e agonists a n d
antagonists
indicates that this research effort has indeed l e d to useful new therapeutic agents, i n c l u d i n g those acting o n p e r i p h e r a l o r endocrine targets as w e l l as centrally acting drugs. I n p a r t i c u l a r , the c a r d i o v a s c u l a r a n d endocrine effects of d o p a m i n e have attracted considerable interest, b o t h f r o m
the
basic a n d a p p l i e d research v i e w p o i n t s . F u r t h e r m o r e , S. S z a b o a n d J . L . N e u m e y e r suggest that the actions of d o p a m i n e i n the
gastrointestinal
tract, a n d its possible etiological role i n peptic ulcers, w i l l represent
an
i m p o r t a n t new focus for future w o r k o n the p e r i p h e r a l actions of d o p a m i n e . T h e availability of p e r i p h e r a l m o d e l s offers an i m p o r t a n t means of characterizing the p h a r m a c o l o g i c a l properties of d o p a m i n e receptors. I n m a n y cases it is possible to measure a clear-cut tissue response a n d , thus, to establish the agonist, p a r t i a l agonist, a n d antagonist properties of test c o m p o u n d s . It is perhaps o n l y n o w b e i n g recognized b y
neurochemists
that receptors cannot be characterized fully i n any other w a y . T e n years ago, w i t h the discovery of n e w b i o c h e m i c a l approaches
to the study of
d o p a m i n e receptors i n C N S m a n y of us were doubtless too o p t i m i s t i c i n t h i n k i n g that s u c h approaches w o u l d l e a d to r a p i d progress i n defining the characteristics of d o p a m i n e receptors. T h e fundamental p r o b l e m i n achieving s u c h understanding, however, has been that we d o not k n o w what d o p a m i n e does as neurotransmitter i n the various C N S pathways that c o n t a i n it. F u r t h e r m o r e , there are n o s i m p l e m o d e l systems
that
a l l o w one to measure agonist a n d antagonist effects o n C N S targets. W e cannot k n o w h o w reliable the results of n e u r o c h e m i c a l studies of d o p a m i n e receptors are i f we have n o b i o l o g i c a l response against w h i c h to assess the n e u r o c h e m i c a l data. A recent r e v i e w ( 7 ) listed some 28 different a p p l i c a -
xi In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
tions of r a d i o l i g a n d b i n d i n g methods to the study of d o p a m i n e receptors i n b r a i n , that use m o r e t h a n twenty different agonist o r antagonist r a d i o ligands. R e m a r k a b l y little is said i n the present v o l u m e about r a d i o l i g a n d b i n d i n g assays, a n d I suspect J . C . Stoof caught the m o o d of the meeting i n stating: " B i n d i n g studies, a l t h o u g h easy to p e r f o r m , have y i e l d e d too m a n y data, too m a n y categories o f d o p a m i n e receptors a n d too m a n y controversies." T h e n e u r o c h e m i c a l emphasis has c l e a r l y shifted to " f u n c t i o n a l " assays, i n w h i c h some b i o c h e m i c a l response is measured,
rather
t h a n s i m p l y o c c u p a t i o n of receptor b i n d i n g sites b y ligands. T h e activation o r i n h i b i t i o n of adenylate cyclase has p r o v e d a v a l u a b l e m o d e l i n this Downloaded by 201.174.74.206 on November 3, 2015 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.pr001
sense, a n d other b i o c h e m i c a l responses m a y p r o v e s i m i l a r l y useful (e.g., i n h i b i t i o n of peptide h o r m o n e o r neurotransmitter release i n response to dopamine agonists). I n this v o l u m e a g o o d deal of emphasis is p l a c e d o n studies of d o p a m i n e receptors i n pituitary. T h i s emphasis seems w e l l justified. T h e clear-cut effects
o f d o p a m i n e i n suppressing p r o l a c t i n secretion
from
anterior l o b e m a m m o t r o p h s , a n d the i n h i b i t o r y effects o n secretion of α - M S H and related secretory products f r o m intermediate l o b e are i m p o r t a n t models for d o p a m i n e receptor studies. I n b o t h cases n e w evidence was put f o r w a r d to support the hypothesis that the actions o f d o p a m i n e o n the secretory cells are mediated b y i n h i b i t i o n of adenylate cyclase. T h i s is far easier to demonstrate i n the intermediate l o b e , w h e r e a l l cells appear to respond to d o p a m i n e , t h a n i n the
anterior lobe, where the
dopa-
mine-sensitive cells p r o b a b l y represent o n l y a s m a l l m i n o r i t y . I n terms of m u l t i p l e receptor categories, the suggestion m a d e b y K e b a b i a n a n d C a l n e ( 2 ) of a d i s t i n c t i o n between D - l a n d D - 2 subtypes, based o n whether the receptors l e a d to s t i m u l a t i o n of adenylate cyclase o r not, has been w i d e l y accepted. It n o w seems that i n m a n y cases (perhaps a l l ) the D - 2 sites are also c o u p l e d to adenylate cyclase, a l t h o u g h i n an i n h i b i t o r y rather t h a n s t i m u l a t o r y manner. A l l of the studies o n pituitary place the d o p a m i n e receptors there clearly i n the D - 2 category. M . C a r o n et a l . , however, report interesting n e w results that indicate that these sites c a n exist i n m o r e than one f o r m — w i t h about h a l f o f the sites i n the resting state i n a f o r m w i t h h i g h affinity for agonists a n d half i n a l o w agonist affinity state. These forms c a n be interconverted, and g u a n y l nucleotide o r N E M treatment shifts the p o p u l a t i o n m a i n l y to the agonist h i g h affinity f o r m . T h i s m a y also help to e x p l a i n the observations of K e b a b i a n et a l . that agonists were far m o r e potent i n intact pituitary c e l l preparations t h a n i n b r o k e n c e l l preparations.
xii In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
T h e r e r e m a i n m a n y difficulties i n further understanding the nature of the different d o p a m i n e receptor categories. W e continue to l a c k suitably selective agonists o r antagonists f o r the D - l a n d D - 2 sites. I n terms of agonists, b r o m o c r i p t i n e a n d related ergoline derivatives are still the most selective D - 2 - s t i m u l a n t s , a n d the series of benzazepines related to S K & F 3 8 3 9 3 are the most p r o m i s i n g D - l - s e l e c t i v e agents ( J . W e i n s t o c k et a l . ) . T h e d i s c o v e r y that benzazepines act i n a stereochemically specific manner, a n d the resolution o f the active and inactive stereoisomeric forms, offers further hope for m o r e selective agonists i n future. D . E . N i c h o l s p r o v i d e s a detailed a n d thoughtful r e v i e w of the m e d i c i n a l chemistry aspects of Downloaded by 201.174.74.206 on November 3, 2015 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.pr001
d o p a m i n e agonist design. T h e r e is still n o D - l - s e l e c t i v e antagonist, a l t h o u g h s u l p i r i d e a n d related benzamides
are w i d e l y u s e d as selective
D-2-antagonists. T h e a v a i l a b i l i t y of at least one tissue m o d e l for D - l receptors, the stimulatory effects of d o p a m i n e o n p a r a t h y r o i d h o r m o n e secretion f r o m b o v i n e p a r a t h y r o i d cells, is of considerable i m p o r t a n c e , but we still have n o c o r r e s p o n d i n g m o d e l to elucidate the possible f u n c t i o n of D - l sites i n the C N S . T h e r e is also considerable difficulty i n relating the b i o c h e m i c a l classification
of D - l a n d D - 2 sites to the p h a r m a c o l o g i c a l l y defined d o p a m i n e
receptor subtypes, described b y L . G o l d b e r g a n d J D . K o h l i , o n the basis of their p a i n s t a k i n g analysis o f agonist/antagonist actions o n c a r d i o v a s c u l a r responses. T h e y describe t w o subcategories of d o p a m i n e receptors,
but
these do not c o r r e s p o n d r e a d i l y to D - l a n d D - 2 sites. T h u s , their " D A i " receptors that cause r e l a x a t i o n of vascular s m o o t h m u s c l e have an agonist specificity s i m i l a r to the D - l sites: w i t h a n absolute requirement f o r a catechol g r o u p i n g ; r i g i d catechol analogues
s u c h as A D T N
are
fully
active; ergolines are inactive. T h e responses are b l o c k e d b y neuroleptics, b u t u n l i k e the D - l site, w h i c h is quite unresponsive to s u l p i r i d e , the D A i receptors are potently b l o c k e d b y sulpiride. T h e " D A " receptors, mediat2
i n g presynaptic c o n t r o l of n o r e p i n e p h r i n e release f r o m sympathetic nerve terminals, resemble D - 2 sites i n their specificity, but again the c o m p a r i s o n is not precise. Interestingly, the D A sites c a n be stimulated even b y some 2
m o n o p h e n o l i c agonists. T h i s is i n t r i g u i n g because some of the n e w l y described "autoreceptor agonists" i n C N S , s u c h as 3 - P P P (3)
are m o n o -
p h e n o l i c structures. T h e t o p i c a l question of whether the receptors l o c a t e d o n the surface of d o p a m i n e neurons i n C N S (autoreceptors)
represent a
u n i q u e p h a r m a c o l o g i c a l class does not perhaps receive as m u c h attention i n this v o l u m e as it s h o u l d have, a l t h o u g h the issue is discussed i n some detail b y J . C . Stoof. A l t h o u g h s u c h receptors c l e a r l y resemble the D - 2 class i n m a n y respects, there remains the s u s p i c i o n that there m a y be some subtle differences.
xiii In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
D e s p i t e the large effort already directed to studies o f d o p a m i n e a n d d o p a m i n e receptors it is clear that m a n y questions r e m a i n unanswered. The
area continues to be one of considerable p r o m i s e a n d i n t e l l e c t u a l
v i g o r a n d f r o m this ferment useful new p h a r m a c o l o g i c a l and, possibly, n e w therapeutic tools m a y eventually emerge.
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Literature
Cited
1. Seeman, P. Pharmac. Rev. 1980, 32, 229-313. 2. Kebabian, J. W.; Calne, D. B. Nature (London) 1979, 277, 93-96. 3. Hjorth, S.; Carlsson, Α.; Wikström, H.; Lindberg, P.; Sanchez, D.; Hacksell, U.; Arvidsson, L. E.; Svensson, U.; Nilsson, J. L. G. Life Sci. 1981, 28, 1225-1238. LESLIE L. IVERSEN
MRC N e u r o c h e m i c a l P h a r m a c o l o g y U n i t M e d i c a l Research C o u n c i l Centre Hills R o a d C a m b r i d g e CB2 2QH, United K i n g d o m
xiv In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.
