2-Amino-6-chloro-4-(N-methylpiperazino)pyrimidines, inhibitors of spiroperidol binding

• Published in: Journal of medicinal chemistry Vol. 25; no. 12; pp. 1459 - 1465
• Main Authors: Gueremy, Claude, Audiau, Francois, Uzan, Andre, Le Fur, Gerard, Leger, Jean Michel, Carpy, Alain
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01-12-1982
• Subjects: Animals; Binding, Competitive - drug effects; Butyrophenones - metabolism; Chemical Phenomena; Chemistry; Clozapine - pharmacology; Corpus Striatum - metabolism; Crystallography; Haloperidol - metabolism; In Vitro Techniques; Molecular Conformation; Piperazines - chemical synthesis; Piperazines - pharmacology; Pyrimidines - chemical synthesis; Pyrimidines - pharmacology; Rats; Receptors, Dopamine - drug effects; Spiperone - metabolism; X-Ray Diffraction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00354a014

A series of 30 6-chloro-2,4-diaminopyrimidines was synthesized and tested in vitro as inhibitors of [3H]spiroperidol binding. The affinity for the dopamine receptor was shown to be related to the 6-chloro-4-(N-methyl-piperazine)pyrimidine structure bearing a NH2 or NHR1 group as a substituent in position 2, provided that R1 was not an alpha branched alkyl group. The nature of the substituent in position 5 is also of importance for the affinity; 2-(benzylamino)-6-chloro-4-(N-methylpiperazino)-5-(methylthio)pyrimidine (22) is the most active member of the series. Molecular structures of three compounds were analyzed by X-ray diffraction and PCILO computation.