ARYL 1-BUT-3-YNYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINES AS POTENTIAL ANTIPSYCHOTIC AGENTS - SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS

A novel series of aryl 1-but-3-ynyl-4-phenyl-1,2,3,6-tetrahydropyridin es with dopaminergic activity is described. The structure-activity rel ationships of this series were studied by synthesis of analogs and eva luation of their affinities for the dopamine (DA) D-2 receptor and inh ibition of locomotor activity (LMA) in rodents. The basic amine, alkyn e chain length, and aryl groups were varied. Compounds having a 4-phen yl-1,2,3,6-tetrahydropyridine and an aryl group with hydrogen-bonding substituents separated by a butynyl chain were found to have the most potent dopaminergic activity. Several compounds that were found to hav e exceptional in vivo activity in LMA inhibition in rodents were evalu ated for additional pharmacological activity including binding affinit ies for other DA receptor subtypes as well as effects on brain DA synt hesis, DA neuronal firing, and conditioned avoidance responding in squ irrel monkeys.