Mapping the dopamine receptor. 1. Features derived from modifications in ring E of the neuroleptic butaclamol

• Published in: Journal of medicinal chemistry 1979-07, Vol.22 (7), p.761-767
• Main Authors: Humber, Leslie G, Bruderlein, Francois T, Philipp, Adolf H, Goetz, Manfred, Voith, Katherine
• Format: Article
• Language: English
• Subjects: Aggression - drug effects; Animals; Avoidance Learning - drug effects; Butaclamol - analogs & derivatives; Butaclamol - chemical synthesis; Butaclamol - metabolism; Butaclamol - pharmacology; Catalepsy - chemically induced; Dextroamphetamine - antagonists & inhibitors; Dibenzocycloheptenes - metabolism; Epinephrine - antagonists & inhibitors; Epinephrine - toxicity; Humans; Male; Methods; Mice; Models, Molecular; Molecular Conformation; Protein Conformation; Rats; Receptors, Dopamine - metabolism; Stereotyped Behavior - drug effects
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00193a003

Several analogues of the neuroleptic agent butaclamol, having modifications in the ring E region of the molecule, have been synthesized. Pharmacological evaluation identified two of the analogues as being equipotent to butaclamol, namely, anhydrobutaclamol (8) and deoxybutaclamol (9a). The molecular structures of both the active and inactive analogues were analyzed and the results have been used for mapping the central dopamine receptor. The existence of a previously proposed lipophilic accessory binding site on the receptor macromolecule has been confirmed. Its minimum dimensions, as well as its locus with respect to the primary binding sites, have been defined. A receptor model incorporating the above features is proposed.