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Identification of dual role of piperazine-linked phenyl cyclopropyl methanone as positive allosteric modulator of 5-HT 2C and negative allosteric modulator of 5-HT 2B receptors.
- Source :
-
European journal of medicinal chemistry [Eur J Med Chem] 2019 Feb 15; Vol. 164, pp. 499-516. Date of Electronic Publication: 2018 Dec 29. - Publication Year :
- 2019
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Abstract
- Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Recent studies have shown that allosteric modulation of serotonin 2C receptor (5-HT <subscript>2C</subscript> ) as a viable strategy for the treatment of various central nervous system (CNS) disorders. Considering the critical role of 5-HT <subscript>2C</subscript> in the modulation of appetite, a selective positive allosteric modulator (PAM) of 5-HT <subscript>2C</subscript> offers a new opportunity for anti-obesity therapeutic development. In this study, phenyl cyclopropyl-linked N-heterocycles were synthesized and evaluated at 5-HT <subscript>2C</subscript> for agonist and PAM activity. Our study shows that imidazole linked phenyl cyclopropyl methanones has PAM activity on both 5-HT <subscript>2C</subscript> and serotonin 2B receptor (5-HT <subscript>2B</subscript> ). Interestingly, piperazine linked phenyl cyclopropyl methanones (58) was active as PAM of 5-HT <subscript>2C</subscript> (increased the E <subscript>max</subscript> of 5-HT to 139%), and as negative allosteric modulator (NAM) of 5-HT <subscript>2B</subscript> (decreases EC <subscript>50</subscript> of 5-HT 10 times without affecting E <subscript>max</subscript> ). Similar effect of compound 58 was observed with synthetic orthosteric agonist lorcaserin on 5-HT <subscript>2B</subscript> . Molecular docking study revealed that all active compounds were binding to the predicted allosteric site on 5-HT <subscript>2C</subscript> and shared a common interacting residues. Finally, compound 58 suppressed food intake in Sprague Dawley (SD) rats similar to lorcaserin after i.c.v. administration. Therefore, these results suggest that piperazine moiety is essential for dual activity (PAM & NAM) of compounds 58, and supports the hypothesis of 5-HT <subscript>2C</subscript> PAM for the treatment of obesity similar to the full agonist.<br /> (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Subjects :
- Animals
Eating drug effects
Heterocyclic Compounds chemical synthesis
Molecular Docking Simulation
Obesity drug therapy
Piperazine chemistry
Rats
Rats, Sprague-Dawley
Allosteric Regulation drug effects
Heterocyclic Compounds pharmacology
Piperazine pharmacology
Receptor, Serotonin, 5-HT2B drug effects
Receptor, Serotonin, 5-HT2C drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1768-3254
- Volume :
- 164
- Database :
- MEDLINE
- Journal :
- European journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30622024
- Full Text :
- https://doi.org/10.1016/j.ejmech.2018.12.070