title: Conformational analysis of 2-substituted piperazines.
abstract: The unusual activity differences of carbon linked versus oxygen linked 2-substituted piperazines as α7 nicotinic acetylcholine receptor agonists led to a conformational study of several examples. The conformational preferences of which are absent from the literature. We report the first study and explanation of the conformational preference of 2-substiturted piperazines and show an example of how this preference controls binding in a pharmaceutically relevant case. In all cases the axial conformation for these 1-acyl and 1 aryl 2-substituted piperazines was found to be preferred. For the ether linked compounds, the axial conformation was found to be further stabilized by an intramolecular hydrogen bond. The axial orientation also places the basic and pyridyl nitrogens into a special orientation that closely mimics nicotine. Molecular modeling studies confirm that the R enantiomers of the compounds can bind to the α7 nicotinic acetylcholine receptor with the basic and pyridyl nitrogens colocalized with their counterparts in Epibatidine.
authors.affiliation: Retrophin, Inc. 12255 El Camino Real, Suite 250, San Diego, CA 92130, United States.
authors.forename: E Adam
authors.initials: EA
authors.lastname: Kallel
authors.affiliation: Retrophin, Inc. 12255 El Camino Real, Suite 250, San Diego, CA 92130, United States.
authors.forename: Colin
authors.initials: C
authors.lastname: Vangel
authors.affiliation: Retrophin, Inc, 301 Binney Street, Cambridge, MA 02142, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Elbaum
mesh_terms: D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000737:chemistry; D006860:Hydrogen Bonding; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D010879:Piperazines / Q000737:chemistry*; D011725:Pyridines / Q000737:chemistry; D013237:Stereoisomerism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D010879:Piperazines; D011725:Pyridines; D064569:alpha7 Nicotinic Acetylcholine Receptor; C082748:epibatidine
keywords: Computational chemistry; Conformational analysis; Piperazines