The stereochemistry of N-methyl and aryl substituents determine the biological activities of 3-aryl-8-methyl-8-azabicyclo[3.2.1]oct-2,3-enes.
Aryl substituted tropanes and their 2,3-ene analogs are highly selective inhibitors of monoamine uptake. The solution structures of a series of aryl tropanes were determined using NMR spectroscopy and molecular modeling to identify conformational preferences that may determine the overall activity. The majority of these analogs undergo nitrogen inversion, and the rate of interconversion between the axial and equatorial N-methyl conformers is fast on the NMR timescale at room temperature but slow between 217 and 243 K allowing us to determine the thermodynamic parameters of interconversion using dynamic and magnetization transfer NMR. The biological activities correlate strongly with the nature and the orientation of the aryl group. The relative orientation of the N-methyl further modulates the activity by directly influencing the ligand interaction in the protein binding pocket and/or by forcing a favorable orientation for the aryl substituent to fit in the binding pocket.
Krunić
Aleksej
A
Department of Medicinal Chemistry & Pharmacognosy, College of Pharmacy MC 781, University of Illinois at Chicago, 833 S. Wood St. Rm 539, Chicago, IL 60612-7231, USA.
Pan
Dahua
D
Dunn
William J
WJ
Mariappan
S V Santhana
SV
D001665:Binding Sites; D015306:Biogenic Monoamines / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D013237:Stereoisomerism; D013696:Temperature; D013816:Thermodynamics; D014326:Tropanes / Q000737:chemistry* / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D015306:Biogenic Monoamines; D014326:Tropanes; D050493:Vesicular Monoamine Transport Proteins