Synthesis and Pharmacological Evaluation of 1-[(1,2-Diphenyl-1<i>H</i>-4-imidazolyl)methyl]-4-phenylpiperazines with Clozapine-Like Mixed Activities at Dopamine D₂, Serotonin, and GABA_AReceptors

Abstract

A series of 18 1-[(1,2-diphenyl-1H-4-imidazolyl)methyl]-4-piperazines (1a−r) were designed and synthesized as possible ligands with mixed dopamine (DA) D2/serotonin 5-HT1A affinity, with the aim of identifying novel compounds with neurochemical and pharmacological properties similar to those of clozapine. The binding profile at D2 like, 5-HT1A, and 5-HT2A receptors of title compounds was determined. Modifications made in the phenyl rings of the parent compound (1a) produced congeners endowed with a broad range of binding affinities for DA D2 like, serotonin 5-HT1A, and 5-HT2A receptors, with IC50 values ranging from 25 to >10 000 nM. As for the modification of the piperazine N4-phenyl ring, the affinities for both D2 like and 5-HT1A receptors were progressively increased by introduction of ortho-methoxy and ethoxy groups (1b,o, respectively). Data revealed the presence of a para-chloro substituent in 1g to be associated with a relatively high affinity and substantial selectivity for D2 like receptors, whereas the meta-chloro analogue 1f exhibited preferential affinity for 5-HT1A receptors. A quantitative structure−affinity relationship analysis of the measured binding data resulted in regression equations that highlighted substituent physicochemical properties modulating the binding to subtypes 1A and 2A of serotonin 5-HT receptors but not to D2 like receptors. Thus, besides an electron-withdrawing field effect and ortho substitution, which both influence binding to serotonin 5-HT receptor subtypes, though to a different extent as revealed by regression coefficients in the multiparametric regression equations, the affinity of congeners 1a−r to 5-HT1A receptors proved to be linearly correlated with volume/polarizability descriptors, whereas their affinity to 5-HT2A receptors correlated with lipophilicity constants through a parabolic relationship. 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-(2-methoxyphenyl)piperazine (1b), with a D2/5-HT1A IC50 ratio of ∼1, was selected for a further pharmacological study. In rats, the intraperitoneal administration of compound 1b, like that of clozapine, induced an increase in the extracellular concentration of DA measured in the medial prefrontal cortex. Furthermore, 1b and clozapine each inhibited GABA-evoked Cl- currents at recombinant GABAA receptors expressed in Xenopus oocytes. These findings suggest that compound 1b may represent an interesting prototype of a novel class of drugs endowed with a neurochemical profile similar to that of atypical antipsychotics.