1. 2-Phenyl-1
- Author
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Marcin, Drop, Vittorio, Canale, Séverine, Chaumont-Dubel, Rafał, Kurczab, Grzegorz, Satała, Xavier, Bantreil, Maria, Walczak, Paulina, Koczurkiewicz-Adamczyk, Gniewomir, Latacz, Anna, Gwizdak, Martyna, Krawczyk, Joanna, Gołębiowska, Katarzyna, Grychowska, Andrzej J, Bojarski, Agnieszka, Nikiforuk, Gilles, Subra, Jean, Martinez, Maciej, Pawłowski, Piotr, Popik, Philippe, Marin, Frédéric, Lamaty, and Paweł, Zajdel
- Subjects
Cdk5 signaling ,inverse agonism ,attentional set shifting task ,Rats ,Structure-Activity Relationship ,Cognition ,5-HT6 receptor ,novel object recognition test ,Receptors, Serotonin ,Animals ,Pyrroles ,constitutive activity ,2-phenyl-1H-pyrrole-3-carboxamide ,Research Article - 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.
- Published
- 2021