title: BU48: a novel buprenorphine analog that exhibits delta-opioid-mediated convulsions but not delta-opioid-mediated antinociception in mice.
abstract: N-Cyclopropylmethyl-[7alpha,8alpha,2', 3']-cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahydronororip avine (BU48) is a novel, ring-constrained analog of buprenorphine. In vivo, BU48 (0.1-10 mg/kg s.c.) produced brief, nonlethal convulsions in mice followed by brief Straub tail and a short period of catalepsy characteristic of BW373U86 and other nonpeptidic delta-receptor agonists. BU48-induced convulsions were sensitive to antagonism by naltrindole (10 mg/kg s.c.) and were also prevented by administration of the putative delta(1) antagonist 7-benzylidenenaltrexone and the putative delta(2) antagonist naltriben, with the latter being more potent. In the abdominal stretch assay in the mouse, only low-efficacy antinociceptive activity of BU48 (0.1-10 mg/kg) was seen. This was reversed by the kappa-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the delta-opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a delta-antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order mu > delta = kappa. In vitro, the compound acted as a potent (EC(50) = 1.4 nM) kappa-opioid agonist in the guinea pig ileum and a potent (EC(50) = 0.2 nM) delta-opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned delta-opioid (40%) and human cloned kappa-opioid (59%) receptors with very low efficacy at the rat cloned mu-opioid receptor (10%); findings consistent with its in vivo profile. BU48 is the first described compound that produces delta-opioid-mediated convulsions without any evidence of delta-opioid-mediated antinociception and will be a useful tool in investigations of the delta-opioid receptor.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
authors.forename: D C
authors.initials: DC
authors.lastname: Broom
authors.forename: L
authors.initials: L
authors.lastname: Guo
authors.forename: A
authors.initials: A
authors.lastname: Coop
authors.forename: S M
authors.initials: SM
authors.lastname: Husbands
authors.forename: J W
authors.initials: JW
authors.lastname: Lewis
authors.forename: J H
authors.initials: JH
authors.lastname: Woods
authors.forename: J R
authors.initials: JR
authors.lastname: Traynor
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D002047:Buprenorphine / Q000031:analogs & derivatives* / Q000494:pharmacology; D003292:Convulsants / Q000494:pharmacology*; D004558:Electric Stimulation; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D010147:Pain Measurement; D010879:Piperazines / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000502:physiology*; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000037:antagonists & inhibitors; D012640:Seizures / Q000139:chemically induced; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D000701:Analgesics, Opioid; C412899:BU 48; D001549:Benzamides; D003292:Convulsants; D009292:Narcotic Antagonists; D010879:Piperazines; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; C088464:4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide; C051844:norbinaltorphimine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D002047:Buprenorphine; D009271:Naltrexone; C055382:naltrindole