A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT1A receptors and α1-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α1-adrenoceptor while both potency and efficacy were increased at the 5-HT1A receptor. A significant improvement of 5-HT1A/α1 selectivity was observed in some of the cyclopentanol derivatives synthesized (4a cis, 4c cis and trans). Compounds 2a and 4c cis emerged as novel and interesting 5-HT1A receptor antagonist (pKi = 8.70) and a 5-HT1A receptor partial agonist (pKi = 9.25, pD2 = 9.03, Emax = 47%, 5- HT1A/α1a = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT1A agonism/antagonism activity.

Synthesis, Biological Evaluation, and Docking Studies ofTetrahydrofuran- Cyclopentanone- and Cyclopentanol-BasedLigands Acting at Adrenergic α1- and Serotonine 5-HT1A Receptors

MARUCCI, Gabriella;BUCCIONI, Michela;
2012-01-01

Abstract

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT1A receptors and α1-adrenoceptor subtypes was measured by binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone, or cyclopentanol moiety leads to an overall reduction of in vitro affinity at the α1-adrenoceptor while both potency and efficacy were increased at the 5-HT1A receptor. A significant improvement of 5-HT1A/α1 selectivity was observed in some of the cyclopentanol derivatives synthesized (4a cis, 4c cis and trans). Compounds 2a and 4c cis emerged as novel and interesting 5-HT1A receptor antagonist (pKi = 8.70) and a 5-HT1A receptor partial agonist (pKi = 9.25, pD2 = 9.03, Emax = 47%, 5- HT1A/α1a = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT1A agonism/antagonism activity.
2012
262
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11581/233279
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