5-HT2C Receptor Stimulation in Obesity Treatment: Orthosteric Agonists vs. Allosteric Modulators

Abstract

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-HT2C receptors (5-HT2CRs), 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-HT2CRs and have been introduced into the clinic as antiobesity medications. Due to their unwanted effects, they were withdrawn from the market. The 5-HT2CR positive allosteric modulators (PAMs) can be potentially safer active drugs than 5-HT2CR 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-HT2CR 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-HT2C receptor” AND “food intake”, and (2) “5-HT2C receptor” AND “obesity” AND “respective agonists”, and (3) “5-HT2C 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.

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“…Furthermore, pediatric use or application in case of pregnancy and lactation have not yet been approved ( 11 ). Due to their severe side effects, including cardiovascular complications, depression, suicidal thoughts, and increased risk of cancer, several weight loss medications, like fenfluramine, dexfenfluramine, sibutramine and lorcaserin were withdrawn from the market ( 26 – 28 ). Bariatric surgery is indicated for BMI over 40 kg/m 2 or BMI greater than or equal to 35 kg/m 2 combined with comorbidity, with studies reporting reduced cardiovascular risk, reduced chronic inflammation, decreased leptin levels, changes in the gut microbiota and long-term remission of T2DM ( 11 , 17 ).…”