Towards next-generation 5-hydroxytryptamine 2C receptor modulators: Greener synthesis and evaluation of novel isocoumarin derivatives as PAAMs of 5-HT2CR

In the current study, we designed a new class of 3-(1-hydroxycycloalkyl)-substituted isocoumarin derivatives as potential modulators of 5-HT_2CR (5-hydroxytryptamine 2C receptor). These compounds were synthesized via a greener as well as faster, milder, and one-pot approach involving the CuCl₂.2H₂O-catalyzed coupling-cyclization of 2-iodobenzoic acid with 1-ethynylcycloalkanols under ultrasound. This ligand and additive-free reaction was completed within 1-1.5 h, affording the desired products in good yields with high regio-selectivity. The environmental sustainability of this protocol was assessed by calculating the key green chemistry metrics, whereas the scalable potential and further application of the methodology were demonstrated. The in vitro evaluation of synthesized compounds revealed that several of them functioned as selective 5-HT_2CR agonists with additional PAAM (positive ago-allosteric modulator) properties (unlike Lorcaserin). Among them, compound 3b demonstrated promising 5HT_2C PAAM activity (EC₅₀ = 8 nM), high metabolic stability in mice brain homogenates (67 % remaining after 2 h), and a favorable (2:1) brain-to-plasma distribution ratio in mice. When evaluated in rats for 22 h, compound 3b reduced food intake at different time points. The molecule also seemed to be safe in both in silico predictions and in vivo experiments. The molecular docking studies of 3b indicated selective engagement with an allosteric binding pocket via H-bonding with Asp134, unlike Lorcaserin (which forms a H-bond with Asn331). Indeed, the ability of 3b to simultaneously anchor through Asp134 and extend into the tripeptide site underlined its novel mechanism for modulating the activity of 5-HT_2CR. Thus, compound 3b emerged as a promising PAAM of 5-HT_2CR for further preclinical assessments. 2009 Elsevier Ltd. All rights reserved.

5HT(2C)R; Food intake; Greener synthesis; Isocoumarin; PAAM.