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[Display omitted] • 3-(1-Hydroxycycloalkyl)isoquinolin-1-ones emerged as potential PAAM of 5-HT 2C R. • These compounds and regioisomeric isoindolin-1-ones were synthesized via Cu-catalysis. • 4i showed PAAM activity for 5-HT 2C R (EC 50 = 1 nM) and selectivity over 2A and 2B. • 4i also showed an acceptable PK and decrease in food intake. • In silico, in vitro and in vivo studies suggested 4i is a promising probe or hit. Efforts have been devoted for the discovery and development of positive allosteric modulators (PAMs) of 5-HT 2C R because of their potential advantages over the orthosteric agonist like Lorcaserin that was withdrawn from the market. On the other hand, pursuing a positive ago-allosteric modulator (PAAM) is considered as beneficial particularly when an agonist is not capable of affecting the potency of the endogenous agonist sufficiently. In search of a suitable PAAM of 5-HT 2C R we adopted an in silico based approach that indicated the potential of the 3-(1-hydroxycycloalkyl) substituted isoquinolin-1-one derivatives against the 5-HT 2C R as majority of these molecules interacted with the site other than that of Lorcaserin with superior docking scores. These compounds along with the regioisomeric 3-methyleneisoindolin-1-one derivatives were prepared via the Cu(OAc) 2 catalyzed coupling of 2-iodobenzamide with 1-ethynylcycloalkanol under ultrasound irradiation. According to the in vitro studies, most of these compounds were not only found to be potent and selective agonists but also emerged as PAAM of 5-HT 2C R whereas Lorcaserin did not show PAAM activities. According to the SAR study the isoquinolin-1(2 H)-ones appeared as better PAAM than isoindolin-1-ones whereas the presence of hydroxyl group appeared to be crucial for the activity. With the potent PAAM activity for 5-HT 2C R (EC 50 = 1 nM) and 107 and 86-fold selectivity towards 5-HT 2C over 5-HT 2A and 5-HT 2B the compound 4i was identified as a hit molecule. The compound showed good stability in male BALB/c mice brain homogenate (∼85 % remaining after 2 h), moderate stability in the presence of rat liver microsomes (42 % remaining after 1 h) and acceptable PK properties with fast reaching in the brain maintaining ∼ 1:1 brain/plasma concentration ratio. The compound at a dose of 50 mg/kg exhibited decreased trend in the food intake starting from day 3 in S.D. rats, which reached significant by 5th day, and the effect was comparable to Lorcaserin (10 mg/kg) on day 5. Thus, being the first example of PAAM of 5-HT 2C R the compound 4i is of further medicinal interest. [ABSTRACT FROM AUTHOR]