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2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT₆ Receptor Inverse Agonists with Cognition-Enhancing Activity.

ABSTRACT: Serotonin type 6 receptor (5-HT₆R) 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 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT₆R. This modification has changed the compound's activity at 5-HT₆R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT₆R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 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, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT₆R inverse agonists.

SUBMITTER: Drop M

PROVIDER: S-EPMC8041276 | biostudies-literature |

REPOSITORIES: biostudies-literature

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