Insights into the Structural Determinants Required for High-Affinity Binding of Chiral Cyclopropane-Containing Ligands to α4β2-Nicotinic Acetylcholine Receptors: An Integrated Approach to Behaviorally Active Nicotinic Ligands

Abstract

Structure-based drug design can potentially accelerate the development of new therapeutics. In this study, a co-crystal structure of the acetylcholine binding protein (AChBP) from Capitella teleta (Ct) in complex with a cyclopropane-containing, selective α4β2-nicotinic acetylcholine receptor (nAChR) partial agonist (compound 5) was acquired. The structural determinants required for ligand binding obtained from this AChBP X-ray structure were used to refine our previous model of the human α4β2-nAChR, thus possibly providing a better understanding of the structure of the human receptor. In order to validate the potential application of the structure of the Ct-AChBP in the engineering of new α4β2-nAChR ligands, homology modeling methods, combined with in silico ADME calculations, were used to design analogs of compound 5. The most promising compound 12, exhibited an improved metabolic stability in comparison to the parent compound 5 while retaining favorable pharmacological parameters together with appropriate behavioral endpoints in the rodent studies.

Synthesis and biological evaluation of novel hybrids of highly potent and selective α4β2-Nicotinic acetylcholine receptor (nAChR) partial agonists

“…While the potency at α4β2 subtypes is excellent, compound 7 also behaved as an agonist at the α7 subtype with a K i value of 136 nM. Substituents at the 5-position of the pyridine core were found to be beneficial for the selectivity for α4β2 over α7 and ganglionic nAChRs, consistent with our own findings employing sazetidine-A analogs[8-11, 13]. In our continued efforts to develop highly selective α4β2-nAChR partial agonists with improved stability, we herein report preliminary SAR findings focused on the incorporation of the diazepane and diazabicycloheptane moieties into our cyclopropyl- or isoxazolylpyridine ether scaffolds.…”

“…Preliminary in vivo evaluation of our nicotinic ligands for behavioral effects relevant to psychiatric diseases was carried out using SmartCube ® , a proprietary, automated assay platform in which behaviors of compound-treated mice are captured by digital video and analyzed with advanced computer algorithms[11, 18-20]. The behavioral signature of a test compound is matched to a database of behavioral signatures previously obtained using a large set of diverse reference compounds, including clinically used antipsychotics, anxiolytics, and antidepressants.…”

“…Previously our group reported the discovery of highly potent and selective α4β2*-nAChR partial agonists containing a cyclopropyl- or isoxazolylpyridine ether scaffold as versatile building blocks for achieving selectivity for α4β2- over α3β4-nAChRs[8-11]. Compounds 3 and 4 bind potently to α4β2-nAChRs ( K i < 1 nM) but not to α3β4*- ( K i > 10 4 nM) and α7-nAChRs ( K i > 10 4 nM) or other neurotransmitter receptors and transporters widely distributed throughout the CNS, while possessing favorable ADMET profiles.…”

Biomolecular recognition of antagonists by α7 nicotinic acetylcholine receptor: Antagonistic mechanism and structure–activity relationships studies

“…Nevertheless, neuronal nAChRs are also confirmed to be connected intimately with many kinds of diseases, e.g. Alzheimer's disease, epilepsy, neurodegeneration and cognitive deficits in Parkinson's disease, and schizophrenia (Changeux and Edelstein, 2005;Zhang et al, 2012;van Arnam and Dougherty, 2014). Normally, it has yielded the viewpoint that neuronal nAChRs exercise a principally regulative effect in the CNS, and this notion has been ratified by several biological proofs (van Arnam et al, 2013;Schaaf, 2014).…”

Characterization of Maleimide-Based Glycogen Synthase Kinase-3 (GSK-3) Inhibitors as Stimulators of Steroidogenesis

“…The behavioral signatures of the test compound were then assessed quantitatively with these classifiers to predict total and specific potential therapeutic utility. 41, 42 …”