Synthesis, biological evaluation and molecular modeling of 1-oxa-4-thiaspiro- and 1,4-dithiaspiro[4.5]decane derivatives as potent and selective 5-HT1A receptor agonists.

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HT1AR agonist with a moderate 5-HT1AR selectivity. In an extension of this work a series of derivatives of 1, obtained by combining different heterocyclic rings with a more flexible amine chain, was synthesized and tested for binding affinity and activity at 5-HT1AR and α1 adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HT1AR partial agonists, the first being outstanding for selectivity (5-HT1A/α1d = 80), the latter for potency (pD2 = 9.58) and efficacy (Emax = 74%). Theoretical studies of ADME properties shows a good profile for the entire series and MDCKII-MDR1 cells permeability data predict a good BBB permeability of compound 15, which possess a promising neuroprotective activity. Furthermore, in mouse formalin test, compound 15 shows a potent antinociceptive activity suggesting a new strategy for pain control.

Synthesis, biological evaluation, and docking studies of tetrahydrofuran- cyclopentanone- and cyclopentanol-based ligands acting at adrenergic α1- and serotonine 5-HT1A receptors.

A series of aralkylphenoxyethylamine and aralkylmethoxyphenylpiperazine compounds was synthesized and their in vitro pharmacological profile at both 5-HT(1A) receptors and α(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 α(1)-adrenoceptor while both potency and efficacy were increased at the 5-HT(1A) receptor. A significant improvement of 5-HT(1A)/α(1) selectivity was observed in some of the cyclopentanol derivatives synthesized (4acis, 4ccis and trans). Compounds 2a and 4ccis 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, pD(2) = 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.