2-Phenyl-1-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT Receptor Inverse Agonists with Cognition-Enhancing Activity.

Serotonin type 6 receptor (5-HTR) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1-pyrrolo[3,2-]quinoline scaffold to provide the 2-phenyl-1-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HTR. This modification has changed the compound's activity at 5-HTR-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound that behaves as an inverse agonist of the 5-HTR at the Gs and Cdk5 signaling pathways. Compound showed high selectivity and metabolic stability and was brain penetrant. Finally, reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1-pyrrole-3-carboxamide might be used as a template for designing 5-HTR inverse agonists.