ABSTRACT
A novel series of arylsulfonamide derivatives of (aryloxy)propyl piperidines was designed to obtain potent 5-HT7R antagonists. Among the compounds evaluated herein, 3-chloro-N-{1-[3-(1,1-biphenyl-2-yloxy)2-hydroxypropyl]piperidin-4-yl}benzenesulfonamide (25) exhibited antagonistic properties at 5-HT7R and showed selectivity over selected serotoninergic and dopaminergic receptors, as well as over serotonin, noradrenaline and dopamine transporters. Compound 25 demonstrated significant antidepressant-like activity in the forced swim test (0.625-2.5mg/kg, i.p.) and in the tail suspension test (1.25mg/kg, i.p.), augmented the antidepressant effect of inactive doses of escitalopram (selective serotonin reuptake inhibitor) and bupropion (dopamine reuptake inhibitor) in the FST in mice, and similarly to SB-269970, exerted pro-cognitive properties in the novel object recognition task in cognitively unimpaired conditions in rats (0.3mg/kg, i.p.). Such an extended pharmacological profile, especially the augmentation effect of the identified 5-HT7R antagonist on SSRI activity, seems promising regarding the complexity of affective disorders and potentially improved outcomes, including mnemonic performance.
Subject(s)
Antidepressive Agents/chemistry , Dopamine Uptake Inhibitors/chemistry , Piperidines/chemistry , Receptors, Serotonin/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Sulfonamides/chemistry , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Binding Sites , CHO Cells , Cognition/drug effects , Cricetinae , Cricetulus , Dopamine Uptake Inhibitors/pharmacology , HEK293 Cells , Humans , Mice , Mice, Inbred C57BL , Molecular Docking Simulation , Phenols/pharmacology , Protein Structure, Tertiary , Rats , Receptors, Serotonin/genetics , Receptors, Serotonin/metabolism , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacologyABSTRACT
A 47-membered library of novel long-chain arylpiperazines, which contained cyclic amino acid amides in the terminal fragment (pyrrolidine-2-carboxamide and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide), was synthesized on Rink-amide resin and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Surprisingly, members of the designed series containing piperidine-2-carboxamide fragments underwent hydrolysis, which occurred during the acidic treatment for release from the solid-support, to their respective pipecolic acid analogs. Representative compounds from the library displayed high-to-low affinity for 5-HT7 (Ki = 18-3134 nM) and 5-HT1A (Ki = 0.5-6307 nM) sites. The possible interactions implicated in binding of the studied compounds to the 5-HT7 receptor were supported by molecular modeling. Research was also applied to support the exploration of the influence of the amide fragment, the length of alkylene spacer, and arylpiperazine substituents on the receptor's affinity and selectivity.
