Binding of arylpiperazines to 5-HT3 serotonin receptors: results of a structure-affinity study

The binding affinities of a series of arylpiperazine derivatives at [3H]quipazine-labeled central 5-HT3 sites were investigated. Features determined to be important for binding include the N4 piperazine nitrogen atom (but not the N1 piperazine nitrogen), and a quinolinyl group. The quinoline nitrogen atom of quipazine also contributes to affinity and its replacement by carbon reduces affinity by 20-fold. The entire quinoline nucleus is not necessary for binding, and certain monocyclic arylpiperazines, particularly those with a chloro group meta to the position of the piperazine ring (e.g. mCPP, MK-212), also bind at 5-HT3, sites; however, the affinities of these agents are at least an order of magnitude less than that of quipazine itself. Taking advantage of the fact that tertiary amines are not well tolerated at 5-HT1B sites, but that N-methyl substituents have little effect on 5-HT3 binding, we designed and synthesized a tertiary amine analog of quipazine, i.e., N-methylquipazine (NMQ). NMQ binds at 5-HT3 sites with an affinity similar to that of quipazine; however, unlike quipazine, NMQ shows very little affinity (IC50 greater than 10,000 nM) for central 5-HT1B sites.