Synthesis, Biological Evaluation, and Docking Studies of Tetrahydrofuran- Cyclopentanone- and Cyclopentanol-Based Ligands Acting at Adrenergic α₁- and Serotonine 5-HT_1A Receptors

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT_1A 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-HT_1A receptor. A significant improvement of 5-HT_1A/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-HT_1A receptor antagonist (pK_i = 8.70) and a 5-HT_1A receptor partial agonist (pK_i = 9.25, pD₂ = 9.03, E_max = 47%, 5-HT_1A/α_1a = 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT_1A agonism/antagonism activity.