Synthesis, Biological Evaluation and Docking Studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at Adrenergic alpha1- and Serotonine 5-HT1A receptors

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT1A receptors and alpha1-adrenoceptor subtypes was measured binding assay and functional studies. The results showed that the replacement of the 1,3-dioxolane ring by a tetrahydrofuran, cyclopentanone or cyclopentanol mojety leads to an overall reduction of in vitro affinity at the alpha1-adrenoceptor while both potency and efficacy were increased at the 5-HT1A receptor. A significant improvement of 5-HT1A/alpha1 selectivity was observed in some of the cyclopentanol derivatives synthesised (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/alpha1a= 69), respectively. Docking studies were performed at support of the biological data and to elucidate the molecular basis for 5-HT1A agonism/antagonism activity.