Dopamine Receptor Microdomains Involved in Molecular Recognition and the Regulation of Drug Affinity and Function

Abstract

A cationic protonatable amine moiety on dopaminergic ligands forms a high affinity reinforced ionic bond with an anionic aspartic acid at position 3.32 of dopamine receptors. When present, catechol hydroxyls of the ligands form hydrogen bonds with serines at position 5.42, 5.43, and 5.46, and this network of hydrogen bonds serves to orient ligands in the binding-site crevice and increase their binding affinity. A steric clash between aromatic moieties of the ligands and aromatic amino acids of the receptor (e.g., H6.55, F6.52 or F6.51 and W6.48) is likely to be propagated in domino-like fashion along the length of TM6, which is believed to trigger activation of the receptor. Specifically, it is the change in the conformation of W6.48 from an orientation perpendicular to the plane of the lipid membrane to one that is parallel that is believed to result in activation. Molecular determinants that mediate the D4/D2-selectivity of many extremely D4-selective 1,4-DAP ligands, include a nonconserved cluster of bulky amino acids at the TM2/TM3 interface (positions 2.61, 3.28 and 3.29).

• G protein-coupled receptors (GPCR)
• Psychiatric disorders
• Neurological disorders
• Structure-function
• Structure-activity relationships (SAR)
• Subtype selective drugs
• Antipsychotics
• Molecular recognition

Abbreviations
L750,667:	=	3-{[4-(4-iodophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine;
L745,870:	=	3-{[4-(4-chlorophenyl) piperazin-1-yl]methyl}-1H-pyrrolo[2,3-b]pyridine and is also known as CPPMA, which stands for chlorophenylpiperazinyl methylazaindole;
NGD 94-1:	=	2-phenyl-4(5)-[4-92-pyrimidinyl)-piperazin-1-yl)-methyl]-imidazole;
FAUC113:	=	3-[4-(4-chlorophenyl)piperazin-1-ylmethyl]pyrazolo [1,5-a]pyridine;
Methylspiperone:	=	8-[4-(4-Fluorophenyl)-4-oxobutyl]-(3-methyl-1-phenyl)-1,3,8-triazaspiro[4,5]decan-4-one hydrochloride;
Ro61-6270:	=	2-Amino-benzoic acid 1-benzyl-piperidin-4-yl ester;
Ro10-4548:	=	RAC-2′-,2-hydroxy-3-4-(4-hydroxy-2-methoxyphenyl)-1-piperazinyl-propoxy-acetanilide;
Dopamine:	=	β-(3,4-dihydroxyphenyl)ethylamine;
Norpropylapo-morphine (NPA):	=	10,11-dihydroxy-N-n-propylnorapomorphine;
Quinpirole:	=	trans-(±)4,4a,5,6,7,8,8a,9-octahydro-5-propyl-1H pyrazolo(3,4-g) quinoline;
Apomorphine:	=	S(+)-10,11-Dihydroxyaporphine;
Sulpiride:	=	(±)-N-1-(Ethylpyrrolidin-2-ylmethyl)-2-methoxy-5-sulfamoylbenzamide or (±)-5-(Aminosulfonyl)-N-[(1 ethyl-2-pyrrolidinyl)methyl]-2-methoxybenzamide
Raclopride:	=	3,5-Dichloro-N-[[(2S)-1-ethyl-2-pyrrolidinyl]methyl]2-hydroxy-6-methoxybenzamide;
Remoxipride:	=	(S)-3-Bromo-N-((1-ethyl-2-pyrrolidinyl)methyl)-2,6-dimethoxybenzamide and is also known as FLA-731; Chlorpromazine, 2-Chloro-10-(3-dimethylaminopropyl)phenothiazine;
Bromocriptine:	=	(5′α)-2-Bromo-12′-hydroxy-2′(1-methylethyl)5′-(2-methylpropyl)ergotamon-3′,6′,18-trione;
Pergolide:	=	8-[(Methylthio)methyl]-6-propylergoline or 8β-([Methylthio]methyl)-6-propylergoline;
R-7-OH DPAT:	=	R-(+)-7-hydroxy-2-(N,N-di-n-propyl-amino)tetralin;
S-5-OH DPAT:	=	S-(–)-5-hydroxy-2-(N,N-di-n-propylamino)tetralin;
N-0437:	=	5-hydroxy-2-(N-n-propyl-N-2-thienylethylamino)tetralin;
SKF 38393:	=	(±)-1-Phenyl-2,3,4,5-tetrahydro-(1H)-3-benzazepine-7,8-diol;
SCH 23390:	=	(R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine;
Clozapine:	=	8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e]-[1,4]-diazepine)
Cis-Flupen- thixol:	=	(Z)-4-(3-[2-(trifluoromethyl)-9H-thioxanthen-9-ylidene]propyl)-1-piperazine-ethanol;
5,6 ADTN:	=	2-amino-5,6-dihydroxy-1,2,3,4-tetrahydronaphthalene;
6,7 ADTN:	=	2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene;
Eticlopride:	=	S(−)-3-Chloro-5-ethyl-N-([1-ethyl-2-pyrrolidinyl]methyl)-6-hydroxy-2-methoxybenzamide;
Dihydrexidine:	=	(DHX) or (trans-10,11-dihydroxy- 5,6,6a,7,8,12b- hexahydrobenzo[a]phenanthridine);
Butaclamol:	=	[3R-(3{α},4a{α},13b{β})]-3-(1,1-dimethylethyl)-2,3,4,4a,8,9,13b,14-octahydro-1H-Benzo[6,7]cyclohepta[1,2,3-de]pyrido[2,1-a]isoquinolin-3-ol (−);
Haloperidol:	=	(4-(4-[p-Chlorophenyl]-4-hydroxy-1piperidinyl)-1-(4-fluorophenyl)-1-butanone;
Epidepride:	=	(S)-N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-iodo-2,3-dimethoxybenzamide;
Risperidone:	=	3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4-H-pyrido[1,2-a]pyrimidin-4-one;
Quetiapine:	=	2-[2-(4-dibenzo[b,f][1,4]thiazepin-11-yl-1-piperazinyl)ethoxy]-ethanol
Olanzapine:	=	2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine;
Ziprasidone:	=	5-(2-(4-(1,2-Benzisothiazol-3-yl)piperazinyl)ethyl)-6-chloro-1,3-dihydro-2(1H)-indole-2-one;
DO710:	=	N-[(1-ethyl-2-pyrrolidinyl)methyl]-2-methoxy-5-[(methylamino)sulfonyl]-Benzamide;
Sultopride:	=	N-[(1-ethyl-2-pyrrolidinyl)methyl]-5-(ethylsulfonyl)-2-methoxy-Benzamide

Notes

^aAll amino acids in this review are referenced with the naming system for GPCRs developed by Ballesteros and Weinstein (1995). Briefly, the most conserved amino acid in the transmembrane helix is denoted by position 50. The naming system for each mutant denotes the wild-type receptor background (D1, D2, D3, or D4) followed by the single letter code for the wild-type amino acid, its location, and amino acid substitution. For example, D4-F2.61V indicates mutation of a phenylalanine at position 61 in TM2 of the D4 dopamine receptor to a valine. From: Ballesteros JA, Weinstein H. 1995. Integrated methods for modeling G-protein coupled receptors. Methods Neurosci 25: 366–428.