STRUCTURE-ACTIVITY RELATIONSHIPS FOR THE BINDING OF ARYLPIPERAZINES AND ARYLBIGUANIDES AT 5-HT3 SEROTONIN RECEPTORS

Arylpiperazines are nonselective agents that bind at 5-HT3 serotonin r eceptors with moderate to high affinity, whereas 1-phenylbiguanide is a low-affinity but more selective 5-HT3 agonist. In an attempt to enha nce the affinity of the latter agent, and working with the assumption that similarities might exist between the binding of the two types of agents, we formulated structure-activity relationships for the binding of the arylpiperazines and then incorporated those substituents, lead ing to high affinity for the arylpiperazines, into 1-phenylbiguanide. A subsequent investigation examined the structure-activity relationshi ps of the arylbiguanides and identified arylguanidines as a novel clas s of 5-HT3 ligands. Although curious similarities exist between the st ructure-activity relationships of the arylpiperazines, arylbiguanides, and arylguanidines, it cannot be concluded that all three series of c ompounds are binding in the same manner. Furthermore, upon investigati ng pairs of compounds in the three series, the arylpiperazines behaved as 5-HT3 antagonists (von Bezold-Jarisch assay) whereas the arylbigua nides and arylguanidines acted as 5-HT3 agonists.