Silvia Franchini1, Leda Ivanova Bencheva1, Umberto Maria Battisti1, Annalisa Tait1, Claudia Sorbi1, Paola Fossa2, Elena Cichero2, Simone Ronsisvalle3, Giuseppina Aricò3, Nunzio Denora4, Rosa Maria Iacobazzi5, Antonio Cilia6, Lorenza Pirona6, Livio Brasili1. 1. Dipartimento di Scienze della Vita, Università degli Studi di Modena e Reggio Emilia, Via Campi 103, 41125 Modena, Italy. 2. Dipartimento di Farmacia, Università degli Studi di Genova, Viale Benedetto XV 3, 16132 Genova, Italy. 3. Dipartimento di Scienze del Farmaco Sezione di Chimica Farmaceutica e Sezione di Farmacologia e Tossicologia, Università degli Studi di Catania, Viale Andrea Doria 6, 95125, Catania, Italy. 4. Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari "Aldo Moro", Via E. Orabona 4, I-70125 Bari, Italy. 5. Istituto tumori IRCCS "Giovanni Paolo II", Via O. Flacco, 65, 70124 Bari, Italy. 6. Divisione Ricerca e Sviluppo, Recordati S.p.A., Via Civitali 1, 20148 Milano, Italy.
Abstract
AIM: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. METHODOLOGY: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.
AIM: Targeting 5-HT1A receptor (5-HT1AR) as a strategy for CNS disorders and pain control. METHODOLOGY: A series of 1,3-dioxolane-based 2-heteroaryl-phenoxyethylamines was synthesized by a convergent approach and evaluated at α1-adrenoceptors and 5-HT1AR by binding and functional experiments. Absorption, distribution, metabolism, excretion and toxicity prediction studies were performed to explore the drug-likeness of the compounds. RESULTS & CONCLUSION: The most promising compound, the pyridin-4-yl derivative, emerged as a potent and selective 5-HT1AR agonist (pKi = 9.2; pD2 = 8.83; 5-HT1A/α1 = 135). In vitro it was able to permeate by passive diffusion MDCKII-MDR1 monolayer mimicking the blood-brain barrier and showed promising neuroprotective activity.
Authors: Kelton L B Dos Santos; Jorddy N Cruz; Luciane B Silva; Ryan S Ramos; Moysés F A Neto; Cleison C Lobato; Sirlene S B Ota; Franco H A Leite; Rosivaldo S Borges; Carlos H T P da Silva; Joaquín M Campos; Cleydson B R Santos Journal: Molecules Date: 2020-03-10 Impact factor: 4.411