Conformation-activity relationships of opiate analgesics.
Extensive conformational calculations were performed on the potent opiate analgesics etorphine, PET, R30490 and etonitazene to determine all of their many low-energy conformations. The results were used to characterize four possible models for binding of a simple pharmacophore, comprising two phenyl rings plus a protonated nitrogen, to opiate analgesic receptors. These four models may define the necessary three-dimensional features leading to particular opiate actions. The model favoured for mu receptor activity can accommodate a protonated nitrogen, an aromatic ring (which may be substituted with an electronegative group) and a second lipophilic group. These structural features must be presented in a precise three-dimensional arrangement. It appears likely that a hydrophilic substituent in a certain region of the analgesic pharmacophore may also interact with the receptor as a secondary binding group.
Martin
J
J
School of Pharmaceutical Chemistry, Victorian College of Pharmacy Ltd., Parkville, Australia.
Andrews
P
P
D000701:Analgesics, Opioid / Q000494:pharmacology*; D001562:Benzimidazoles / Q000494:pharmacology; D003196:Computer Graphics; D005048:Etorphine / Q000494:pharmacology; D005283:Fentanyl / Q000031:analogs & derivatives / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011957:Receptors, Opioid / Q000187:drug effects; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D001562:Benzimidazoles; D011957:Receptors, Opioid; D005048:Etorphine; C058443:4-methoxymethylfentanyl; D005283:Fentanyl