title: New 1-(heterocyclylalkyl)-4-(propionanilido)-4-piperidinyl methyl ester and methylene methyl ether analgesics.
abstract: A series of new 1-(heterocyclyalkyl)-4-(propionanilido)-4-piperidinyl methyl esters and methylene methyl ethers have been synthesized and pharmacologically evaluated. In the mouse hot-plate test, the majority of compounds exhibited an analgesia (ED50 less than 1 mg/kg) superior to that of morphine. These studies revealed a pharmacological accommodation for many more structurally diverse and far bulkier aromatic ring systems than the corresponding components of the arylethyl groups of the prototypic methyl ester (carfentanil, 2) and methylene methyl ether (sufentanil, 3 and alfentanil, 4) 4-propionanilido analgesics. Compound 9A (methyl 1-[2-(1H-pyrazol-1-yl)-ethyl]-4-[(1-oxopropyl)phenylamino]-4- piperidinecarboxylate), which exhibited appreciable mu-opioid receptor affinity, was a more potent and short-acting analgesic, than alfentanil with less respiratory depression in the rat. On the other hand, the phthalimides 57A and 57B, which exhibited negligible affinity for opioid receptors associated with the mediation of nociceptive transmission (i.e., mu-, kappa-, and delta-subtypes), displayed analgesic efficacy in all antinociception tests. In addition, while 57B, compared to clinical opioids, showed a superior recovery of motor coordination after regaining of righting reflex from full anesthetic doses in the rat rotorod test, 57A showed significantly less depression of cardiovascular function at supraanalgesic doses in the isoflurane-anesthetized rat.
authors.affiliation: Chemistry Department, Anaquest, Inc., A BOC Health Care Company, Murray Hill, New Jersey 07974.
authors.forename: J R
authors.initials: JR
authors.lastname: Bagley
authors.forename: S A
authors.initials: SA
authors.lastname: Thomas
authors.forename: F G
authors.initials: FG
authors.lastname: Rudo
authors.forename: H K
authors.initials: HK
authors.lastname: Spencer
authors.forename: B M
authors.initials: BM
authors.lastname: Doorley
authors.forename: M H
authors.initials: MH
authors.lastname: Ossipov
authors.forename: T P
authors.initials: TP
authors.lastname: Jerussi
authors.forename: M J
authors.initials: MJ
authors.lastname: Benvenga
authors.forename: T
authors.initials: T
authors.lastname: Spaulding
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007539:Isonicotinic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D051379:Mice; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D007539:Isonicotinic Acids; D011720:Pyrazoles; D011957:Receptors, Opioid