TY - JOUR
T1 - Stereochemical Studies on Medicinal Agents. 25. Absolute Configuration and Analgetic Potency of β-1,2-Dimethyl-4-phenyl-4-(propionyloxy)piperidine Enantiomers
AU - Fries, David S.
AU - Dodge, Richard P.
AU - Hope, Hakon
AU - Portoghese, Philip S.
PY - 1982/1/1
Y1 - 1982/1/1
N2 - Enantiomers of β-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine (4) were employed as probes to demonstrate that opioid receptors are capable of distinguishing between the enantiotopic edges (the Ogston effect) of the piperidine ring. These enantiomers, (−)- and (+)-4·HCl, were prepared by esterification of the corresponding alcohols, (+)-and (−)-4a. Single crystal X-ray studies of (−)-4a·HCl reveal that it possesses the 2R,4S absolute configuration. Analgetic testing in mice (hot-plate) and receptor binding studies indicate that (−)-(2S,4R)-4·HCl is approximately ten times more potent than its enantiomer. The results are consistent with the operation of the Ogston effect in the interaction of achiral 4-phenylpiperidines with opioid receptors. Additionally, it is suggested that the piperidine ring of these and other closely related 4-phenylpiperidines bind within a receptor subsite cleft whose dimensions exclude diequatorial 2,6- and 3,5-dimethyl-substituted ligands.
AB - Enantiomers of β-1,2-dimethyl-4-phenyl-4-(propionyloxy)piperidine (4) were employed as probes to demonstrate that opioid receptors are capable of distinguishing between the enantiotopic edges (the Ogston effect) of the piperidine ring. These enantiomers, (−)- and (+)-4·HCl, were prepared by esterification of the corresponding alcohols, (+)-and (−)-4a. Single crystal X-ray studies of (−)-4a·HCl reveal that it possesses the 2R,4S absolute configuration. Analgetic testing in mice (hot-plate) and receptor binding studies indicate that (−)-(2S,4R)-4·HCl is approximately ten times more potent than its enantiomer. The results are consistent with the operation of the Ogston effect in the interaction of achiral 4-phenylpiperidines with opioid receptors. Additionally, it is suggested that the piperidine ring of these and other closely related 4-phenylpiperidines bind within a receptor subsite cleft whose dimensions exclude diequatorial 2,6- and 3,5-dimethyl-substituted ligands.
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U2 - 10.1021/jm00343a002
DO - 10.1021/jm00343a002
M3 - Article
C2 - 6283082
AN - SCOPUS:0020054481
SN - 0022-2623
VL - 25
SP - 9
EP - 12
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 1
ER -