Structure-Activity Relationships in the Actions of 1-Phenyl-Piperazines on Brain Serotonin Receptors

Abstract

Several compounds containing a 1-phenyl-piperazine moiety have been reported to interact with central serotoninergic systems. For example, trazodone, 2-(3-[4-(m-chlorophenyl)-1piperazinyl]propyl)-S-triazolo-[4,3-a]pyridin-3[2H]-one (Fig. 1), has been variously described as a serotonin uptake inhibitor, agonist, and antagonist (Silvestrini et al, 1968; Garattini et al, 1976; Maj et al, 1979). Mepiprazole, 1-(m-chlorophenyl)-4[2-(5-methyl-3-pyrazolyl)-ethyl]-piperazine (Fig. 1), has been claimed to increase serotonin concentration at the receptor site by a combination of neuronal uptake inhibition and release (Placheta et al, 1975), and Fuxe et al (1976) have suggested that mepiprazole causes extragranular release of serotonin stores. Related compounds with a simpler structure have also been studied. For example, 1-(m-chlorophenyl)-piperazine, a possible metabolite of trazodone (and of mepiprazole), was observed to inhibit serotonin uptake more potently than trazodone (Garattini et al, 1976). l-(m-Trifluoromethylphenyl)-piperazine has been reported to have serotonin agonist activity (Fuller et al, 1978; Fuller and Clemens, 1979). Quipazine and MK-212 are serotonin agonists (Rodriguez et al, 1973; Clineschmidt et al, 1977) that are 1-aryl-piperazines but not 1-phenyl-piperazines (see Fig. 1). Because of these reports, we have undertaken a study of various substituted 1-phenyl-piperazines and related compounds to determine their ability to act directly on serotonin receptors as indicated by their competition with ³H-serotonin for binding to membranes from rat brain in vitro. These effects and others of some 1-phenyl-piperazines are described herein.