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.

Recently, 1-(1,4-dioxaspiro[4,5]dec-2-ylmethyl)-4-(2-methoxyphenyl)piperazine (1) was reported as a potent 5-HTR agonist with a moderate 5-HTR 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-HTR and α adrenoceptors. The results led to the identification of 14 and 15 as novel 5-HTR partial agonists, the first being outstanding for selectivity (5-HT/α = 80), the latter for potency (pD = 9.58) and efficacy (E = 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.

Heteroaryl ortho-phenoxyethyl amines have been extensively employed in medicinal chemistry as privileged scaffolds for the design of highly potent and selective ligands. Herein we report an efficient, fast and general method for the synthesis of heteroaryl phenoxyethyl amines via Suzuki cross-coupling. This approach offers the opportunity to obtain a large variety of biaryls incorporating five-membered (thiophene, furan, thiazole, pyrazole, imidazole) or six-membered (pyridine, pyrimidine) heteroaromatic rings for appropriate libraries of ligands. All the compounds presented here have never been synthesized before and a full structural characterization is given

Chemistry. -(MANASIEVA, L. I.; MARIA, B. U.; PRANDI, A.; BRASILI, L.; FRANCHINI*, S.; Synthesis 47 (2015) 23, 3767-3775, http://dx.doi.org/10.1055/s-0035-1560456 ; Dip Sci. Vita, Univ. Stud. Modena, I-41125 Modena, Italy; Eng.) -F. Schill 16-087