5-HT2C Receptor Agonists for the Treatment of Obesity. Biological and Chemical Adventures

Abstract

Obesity is a major risk factor in the development of conditions such as hypertension, hyperglycemia, dyslipidemia, coronary artery disease and cancer. There is increasing evidence suggesting an important role for the 5-HT 2C receptor in appetite control. Collaboration between F. Hoffmann-La Roche Ltd and Vernalis Research Ltd has allowed rapid construction of a solid structure-activity relationship around a pyrroloindole core. A one-pot Sonogashira reaction followed by nucleophilic double cyclisation allows an elegant and expedient route to this central motif. Introduction of a (2S)-aminopropyl group in place of the aminoethyl endogenous ligand side-chain enhanced the affinity at the 5-HT 2C receptor and reduced affinity towards monoamine oxidase enzymes (MAO). Sulfamidate reagents were found to be very effective for the introduction of the 2-aminopropyl moiety in a stereoselective manner. The substitution at position 5 (indole numbering) was found to be crucial for both affinity and selectivity. Pyrroloindoles bearing an alkoxyether in this position exhibit promising pharmacokinetic parameters in rodent and significant reduction of food intake, after per os application.

Focused library design in GPCR projects on the example of 5‐HT2c agonists: Comparison of structure‐based virtual screening with ligand‐based search methods

“…Besides the salt bridge between the basic amine of the 5‐HT 2c agonists and Asp3.32, the agonists seem to interact with the receptor mainly via hydrophobic interactions. Accordingly, the 5‐HT 2c agonist pharmacophore consists only of a positively charged amine, an aromatic ring, and an additional hydrophobic substituent 30. Additionally, the known 5‐HT 2c agonists are rather small, rigid molecules.…”

Design, synthesis, biological evaluations, molecular docking, and in vivo studies of novel phthalimide analogs

“…Tryptamine (indole‐3‐ethylamine) and its derivatives have high pharmaceutical significance because of their naturally occurring as well as their utility in several drugs . Tryptamine derivatives are used in the treatment of migraine, obesity and behave as antitumor active analogs …”

Biological and structural properties’ interpretation on antitumour drug 3-(2-aminoethyl) indole (tryptamine) using molecular spectroscopy and computational tools

“…Tryptamine is monoamine alkaloid and essentially behaves as a neurotransmitter also used as a psychedelic drug [4,5]. Though it has 5-hydroxytryptamine receptors' agonist activity [6], tryptamine is acting as an antitumour agent due to its high cytotoxicity [7,8]. It is also used for the treatment of migraine and obesity with its high pharmacological indices [9].…”