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 (<b>4a</b> <i>cis</i>, <b>4c</b> <i>cis</i> and <i>trans</i>). Compounds <b>2a</b> and <b>4c</b> <i>cis</i> emerged as novel and interesting 5-HT_1A receptor antagonist (p<i>K</i>_i = 8.70) and a 5-HT_1A receptor partial agonist (p<i>K</i>_i = 9.25, pD₂ = 9.03, <i>E</i>_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

5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors

The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3-dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2<i>H</i>-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood–brain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPAr-positive modulator candidates