Renal Vascular Dopamine Receptor Topography - ACS Symposium

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Renal Vascular Dopamine Receptor Topography Structure-Activity Relationships That Suggest the Presence of a Ceiling P A U L W. E R H A R D T American Critical Care, McGaw Park, IL 60085

A topographical model has been proposed to e x p l a i n why (E)-2-(3,4-dihydroxyphenyl)cyclopropylamine, 1, and alpha-methyldopamine (AMDA) are i n a c t i v e i n the r e n a l v a s c u l a r dopamine (DA) receptor system. In t h i s model a s t e r i c p r o t r u s i o n (S2) r e s i d e s approximately 2Å above the g e n e r a l i z e d plane of the receptor and acts to impede i n t e r a c t i o n with molecules such as 1 and AMDA which possess a d d i t i o n a l bulk i n t h i s r e g i o n . Recent developments i n DA 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 o f f e r f u r t h e r support f o r the e x i s t e n c e of the S2 s i t e . The close s t r u c t u r a l s i m i l a r i t y of the s e m i r i g i d conformat i o n a l analogue 1 to the trans-rotamer of dopamine (DA) was noted almost ten years ago (1,2). The s y n t h e s i s of 1 has been described more r e c e n t l y and i t s pharmacological p r o f i l e determined (3-6) to be s i m i l a r to alpha-methyldopamine (AMDA) which i s i n a c t i v e as a dopaminergic agent.

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0097-6156/83/0224-0275$06.00/0 © 1983 American Chemical Society In Dopamine Receptors; Kaiser, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 5, 2015 | http://pubs.acs.org Publication Date: June 29, 1983 | doi: 10.1021/bk-1983-0224.ch012

276

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RECEPTORS

I t has been suggested (7) that AMDA l a c k s dopaminergic a c t i v i t y because i t s a r y l - r i n g cannot achieve approximate c o p l a n a r i t y with i t s s i d e chain as required (8,9,10) f o r optimal i n t e r a c t i o n with DA receptors. However, i n AMDA the side chain carbon bonds, and i n 1 the bond between the beta-carbon and c a t e c h o l , are a l l f r e e to r o t a t e with only minimal thermodynamic c o n s t r a i n t (11). Therefore, conformational arguments seem an u n l i k e l y explanation f o r the i n a c t i v i t y observed f o r these compounds. A l t e r n a t i v e l y , i t has been suggested that the molecular bulk added by the methylene i n 1 and the methyl i n AMDA i n t e r f e r e s with receptor i n t e r a c t i o n because a s t e r i c p r o t r u s i o n r e s i d e s above the general plane of the receptor i n a proposed (12) topographical model. Examination of considerable DA agonist 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 (SAR), with s p e c i f i c c o n s i d e r a t i o n of the c e n t r a l chain region, revealed that while aryl-amine near c o p l a n a r i t y i s a feature common to a l l of these agents, the c e n t r a l chain v a r i e s considerably from the common plane r e l a t i o n s h i p . This became an important d i s t i n c t i o n from the p r i o r a r t since i n the receptor model there i s then no requirement f o r agonists to approach an a n t i p e r i p l a n a r conformational arrangement or to achieve an approximate 180° d i h e d r a l angle. For example, c e r t a i n indanamine d e r i v a t i v e s (1,8) possess aryl-amine c o p l a n a r i t y when assuming an envelope conformation (13), and c e r t a i n benzazepine d e r i v a t i v e s (14) can assume a favored (15) p a r t i a l l y e c l i p s e d conformation i n which the amine f u n c t i o n l i e s w i t h i n the plane e s t a b l i s h e d by the catechol r i n g . F i n a l topographical features f o r t h i s receptor model were provided by aporphine SAR. I t has been suggested (16) that the Α-ring o f apomorphine (APO) a s s o c i a t e s with an a u x i l i a r y hydrophobic binding s i t e . A l t e r n a t i v e l y , to e x p l a i n the i n a c t i v i t y of isoapomorphine (ISO) i t has been suggested (16,17, 18) that t h i s same r i n g r e s i d e s i n a receptor region l i m i t e d by a s t e r i c boundary. The d i f f e r e n c e between these compounds i s that i n APO the Α-ring i s on the same s i d e as the analogous DA meta-hydroxy group while i n ISO t h i s r i n g i s opposite to the analogous meta-hydroxy group. This d i f f e r e n c e becomes apparent when an attempt i s made to place APO and ISO i n the receptor model as depicted i n Figure 1. Examination of recent DA SAR f u r t h e r supports the existence of an S2 s i t e . Several new compounds, 2-7, contain s t e r i c bulk i n regions n e a r l y superimpοsable with that i n 1 and AMDA, as i l l u s t r a t e d by the arrow next to t h e i r Newman p r o j e c t i o n s . Although many of these s t r u c t u r e s are h e l d i n p u t a t i v e i d e a l conformations, t h e i r i n d i c a t e d bulk would be expected to c o l l i d e with s i t e S2 i n Figure 1. A l l of these s t r u c t u r e s have been determined (19-24) t o be e s s e n t i a l l y i n a c t i v e i n dopaminergic t e s t systems. To date, t h i s author has not found a potent p e r i p h e r a l or c e n t r a l DA agonist s t r u c t u r e which manifests s i g n i f i c a n t bulk i n the receptor region designated as S2.

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

ERHARDT

Renal Vascular Dopamine Receptor

Topography


12.


277


278 DOPAMINE RECEPTORS



12.

ERHARDT

Figure 1.

Renal Vascular Dopamine

Receptor

Topography

279

Topographical model of the renal vascular dopamine receptor (12).

Features include: 1, a single plane containing amine (A) and catechol (C, H , H ) recognition sites (the distances between A and H and A and H approximate 7 A; the plane extends across the analogous central chain region and can be thought of as the "floor" of the receptor); 2, a steric parameter, SI ("rear wall"), located in the —x, -fy quadrant and a steric parameter, S2 ("ceiling"), centered specifically near x, 0.0; y, 1.5; z, 2.5; and 3, an auxiliary hydrophobic or lipophilic binding site (B) located in the -\-x, +y quadrant. With refinement, Site A can be moved to a more specific location approximately 0.2 Â above the x-y plane and the nature of Site C need not be specifically defined as a recognition or binding site. The rigid representation in this model is not meant to imply that a more dynamic relationship, such as mutual molding, is not operative during drug-receptor interaction. (Reproduced with permission from Ref. 12. Copyright 1980, American Pharmaceutical Association.) m

m

P

P


280

DOPAMINE RECEPTORS

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Renal Vascular Dopamine Receptor Topography - ACS Symposium

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