Identification of substituted pyrazole constrained arylpiperazines asselective ligands for serotonin 5HT1aand 5HT2areceptors
Bulletin of the Korean Chemical Society (Print)
Neurotransmitters, dopamine and serotonin play important roles in the development of neurological and psychiatric disorders such as schizophrenia 1 and depression. 2 Extensive efforts have been made to explore potent and selective ligands of subtype dopamine D 3 3 or D 4 4 receptor for the discovery of antipsychotic drugs. 5 In continuation of search for selective ligands for various GPCRs, we have recently reported 6 the design and synthesis of arylpiperazine derivative libraries with
... rings for antagonist of dopamine and serotonin receptors. We envisaged that attaching aryl group to one of the nitrogen atoms of the pyrazole ring with proper alkyl linker between pyrazole and piperazine rings would provide a well defined constraint to the spatial orientation of aryl groups and the biogenic nitrogen. With this envision in mind, we designed and synthesized a focused library of aryl piperazine derivatives of phenyl substituted pyrazole ring with methoxymethyl substituent (Scheme 1). Herein we wish to report preparation of a series of arylpiperazine derivatives of pyrazole, and identification of compounds that show high selectivity for subtype serotonin receptor s 5HT 1a and 5HT 2a as well as D 3 and 5HT 7 . The pyrazolyl arylpiperazines 8-11 were synthesized from methoxyacetone 1 as shown in the Scheme 1. 7 Table 1 shows the binding data of the compounds with interesting selectivity profile mainly for 5HT 1a and 5HT 2a receptors and somewhat for D 3 , D 4 and 5HT 7 receptors. 8 While the anti-isomer with phenylpiperazine, 8a shows good selectivity for 5HT 1a syn-isomer 9a shows selectivity for 5HT 2a . When phenyl group of the piperazine ring of the anti-isomer 8a was substituted at the ortho-position, the binding affinity for 5HT 1a improved regardless of the electronic nature of the substituent (8b and 8h) . The electron donating substituent shows binding activity for D 3 and 5HT 7 (8h), while electron withdrawing substituent shows good selectivity only for 5HT 1a (8b). When the chain length between piperazine ring and pyrazole was shortened from four to three, binding activity for 5HT 1a has decreased by ten folds (10h). When the substituent was introduced at the meta-position, similar increase in binding activity for 5HT 1a was observed along with improvement in the binding activity for 5HT 7 (8c). Replacing phenyl ring with 2-pyridyl ring (8e) showed the similar effect to the compound with electron withdrawing ortho-substitutent (8b). When both orthoand meta-positions were substituted no synergistic or additive effect was observed. Instead, there showed improvement † This paper is dedicated to Professor Eun Lee on the occasion of his honourable retirement.