Synthesis and receptor binding of enantiomeric N-substituted cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamines as high-affinity sigma receptor ligands.
N-Alkyl-substituted derivatives of (+)- and (-)-cis-N-[2-(3,4-dichlorophenyl)ethyl]-2-(1-pyrrolidinyl)cyclohexylamin e have been synthesized in nine steps in a stereospecific manner starting from cyclohexene oxide. The key step in the reaction sequence involved catalytic hydrogenation of oxime 8 in the presence of PtO2 and AcOH to give the cis diamine (+/-)-7. Most of the compounds in this series exhibited very high affinity at sigma receptors when tested against [3H]-(+)-3-PPP, and in general it was observed that the 1R,2S enantiomers bound more potently to sigma receptors than their corresponding 1S,2R enantiomers. The most potent sigma ligand found in this class was the unsubstituted derivative (1R,2S)-(-)-4, which exhibited an affinity constant of 0.49 nM. This compound was also found to be very selective for sigma receptors. It exhibited little or no affinity for kappa opioid, PCP, and dopamine-D2 receptors. It was also demonstrated that the cis configuration as opposed to the trans configuration of (+)- and (-)-5 was necessary for a higher sigma receptor affinity.
Radesca
L
L
Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
Bowen
W D
WD
Di Paolo
L
L
de Costa
B R
BR
D003514:Cyclohexylamines / Q000737:chemistry* / Q000378:metabolism; D008968:Molecular Conformation; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003514:Cyclohexylamines; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta