Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 55, Issue 1, Pages 23-36Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm200421e
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- University of Modena and Reggio Emilia
- MIUR
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A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT1A receptors and alpha(1)-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 alpha(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT1A receptor. A significant improvement of 5-HT1A/alpha 1 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 (pK(i) = 8.70) and a 5-HT1A receptor partial agonist (pK(i) = 9.25, pD(2) = 9.03, E-max = 47%, 5-HT1A/alpha 1a = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT1A agonism/antagonism activity.
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