CNS Drug Discovery & Therapy
(Track) NOVEL POSITIVE ALLOSTERIC MODULATORS OF THE HUMAN α7 NICOTINIC RECEPTOR MODULATE THE ANTIDEPRESSANT ACTIVITY ELICITED BY NICOTINE Krzysztof Jóźwiak, Katarzyna M. Targowska-Duda, Hugo R. Arias and Dominik Feuerbach Head of Laboratory of Medicinal Chemistry and Neuroengineering, Department of Chemistry, Faculty of Pharmacy, Medical University of Lublin, ul. Chodźki 4a 4, 20-093 Lublin, Poland Nicotinic acetylcholine receptors (AChRs) are archetypical members of the Cys-loop Ligand Gated Ion Channels superfamily. AChRs are promising targets for the treatment of many neurological disorders, including Alzheimer’s disease, depression, and drug addiction, to name a few of them [1]. Major Depressive Disorder is extremely prevalent in the U.S. population (~20%) and one of the leading causes of disability and morbidity in the world [2]. The aim of this study is to characterize the structural and functional interactions of novel positive allosteric modulators (PAMs) with different AChRs, and to determine its modulatory activity on nicotine induced antidepressant effects in mutant mice. Ca2+ influx results indicate that these compounds are not agonists of the human (h) α4β2, α3β4, α7, and α1β1γδ AChRs [3]. Compounds 2-4 are specific PAMs of hα7 AChRs, whereas compounds 1-4, 7, and 12 are noncompetitive antagonists of the other AChRs. Radioligand binding results show that these PAMs enhance [3H]epibatidine binding to hα7 AChRs, indicating that these compounds do not directly, but allosterically, interact with the hα7 agonist sites [3]. Molecular dynamics and docking results suggest that the binding site for PAMs 2-4 is mainly located in the inner β-sheet of the α7-α7 interface, ~12 Å from the agonist locus. Two hydrogen bond interactions bridging both (+) and (-) subunit faces are found to be critical for the PAM activity at the hα7 AChR [3]. Based on the forced swimming tests (FST) on mutant (b4-/-) and wild-type (b4+/+) mice, male vs female, we determined that: (1) the b4 subunit plays an important role in the antidepressant effect elicited by nicotine. The results indicated a statistically significant increase of the antidepressant effect of nicotine in β4+/+ mice compared to β4-/- mice, and (2) PAM-2 modulates this activity in a gender distinct manner. The results indicated that PAM-2 enhances the antidepressant effect of nicotine in female β4+/+ mice but diminishes it in male β4+/+ mice. In β4-/- mice, the statistically significant increase of the antidepressant effect (chronic) of nicotine in PAM-2 treated mice compared to only nicotine treated mice. The receptor specificity and the modulatory action on nicotine-induced antidepressant activity elicited by PAMs 2-4 might be therapeutically important for the treatment of depressed patients with Alzheimer’s disease. |