5-HT(2C) Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators

Obesity is a substantial health and economic issue, and serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter system involved in the regulation of body weight. The 5-HT(2C) receptors (5-HT(2C)Rs), one of 16 of the 5-HT receptor (5-HTRs) subtypes, play a significant role in food intake and body weight control. In this review, we focused on the 5-HTR agonists, such as fenfluramines, sibutramine, and lorcaserin, which act directly or indirectly at 5-HT(2C)Rs and have been introduced into the clinic as antiobesity medications. Due to their unwanted effects, they were withdrawn from the market. The 5-HT(2C)R positive allosteric modulators (PAMs) can be potentially safer active drugs than 5-HT(2C)R agonists. However, more in vivo validation of PAMs is required to fully determine if these drugs will be effective in obesity prevention and antiobesity pharmacology treatment. Methodology strategy: This review focuses on the role of 5-HT(2C)R agonism in obesity treatment, such as food intake regulation and weight gain. The literature was reviewed according to the review topic. We searched the PubMed and Scopus databases and Multidisciplinary Digital Publishing Institute open-access scientific journals using the following keyword search strategy depending on the chapter phrases: (1) “5-HT(2C) receptor” AND “food intake”, and (2) “5-HT(2C) receptor” AND “obesity” AND “respective agonists”, and (3) “5-HT(2C) receptor” AND “PAM”. We included preclinical studies (only present the weight loss effects) and double-blind, placebo-controlled, randomized clinical trials published since the 1975s (mostly related to antiobesity treatment), and excluded the pay-walled articles. After the search process, the authors selected, carefully screened, and reviewed appropriate papers. In total, 136 articles were included in this review.