deschloroepibatidine and 3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole

The homology models of the extracellular domains of the neuronal alpha4beta2 (pdb code: 1ole) and ganglionic alpha3beta4 (pdb code: 1olf) rat nicotinic acetylcholine receptor (nAChR) subtypes were refined and energetically minimized. In this work, a series of nAChR ligands (1-15) were docked into the modeled binding cavity of both receptors. High-affinity, toxic ligands such as epibatidine (1) and dechloroepibatidine (2) docked into cluster 1 with the charged tertiary amino group, forming a pi-cation interaction with Trp 147 on the (+) side of the alpha4 subunit and establishing a characteristic H-bond with the Lys 77 on the (-) side of the beta2 subunit. The nontoxic ligands such as 33bMet (3), (S)-A-85380 (4), and acetylcholine (6) docked into cluster 2 with the same pi-cation interaction but with the rest of the molecule occupying a different moiety of the binding pocket. Molecular docking into the alpha3beta4 subtype showed that both enantiomers of 1 (1a and 1b) are representative templates for ligands with affinity toward this ganglionic nAChR subtype. The ranking scores of the docked molecules confirm the existence of structure-dependent subtype selectivity and shed light on the design of specific and selective alpha4beta2 nAChR subtype ligands.

Topics: Acetylcholine; Animals; Azetidines; Binding Sites; Binding, Competitive; Brain; Bridged Bicyclo Compounds, Heterocyclic; Cell Line; Crystallography, X-Ray; Hydrogen Bonding; In Vitro Techniques; Isoxazoles; Ligands; Mice; Models, Molecular; Nerve Tissue Proteins; Oocytes; Pyridines; Pyrrolidines; Rats; Receptors, Nicotinic; Snails; Stereoisomerism; Thermodynamics; Xenopus