Synthesis and pharmacological studies of 4,4-disubstituted piperidines: a new class of compounds with potent analgesic properties.
A series of 4,4-disubstituted piperidines has been synthesized and evaluated for analgesic activity. Several of these analogues show analgesic potency comparable to morphine in the mouse writhing and tail-flick tests. A number of compounds exhibit high affinity for [3H]naloxone binding sites in rat brain membranes. Among the most potent derivatives are compounds 15 and 48. Although opiate-like, attempts to modify this activity with various substituents have failed to produce antagonistic properties. A few of these analogues also show marked long-lasting serotonin antagonism in the guinea pig serotonin toxicity test and the DL-5-hydroxytryptophan induced head-twitch model in the mouse.
D006916:5-Hydroxytryptophan / Q000494:pharmacology; D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D001667:Binding, Competitive; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008566:Membranes / Q000378:metabolism; D051379:Mice; D009270:Naloxone / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011930:Reaction Time / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000700:Analgesics; D010880:Piperidines; D012702:Serotonin Antagonists; D009270:Naloxone; D006916:5-Hydroxytryptophan