Abstract
N-Cyclopropylmethyl-[7α,8α,2′,3′]-cyclohexano-1′[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine (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 δ-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 δ1 antagonist 7-benzylidenenaltrexone and the putative δ2 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 κ-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not by the δ-opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10 mg/kg s.c.) acted as a δ-antagonist in this assay. In mouse brain homogenates, BU48 had high (nanomolar) binding affinity for all three opioid receptors in the order μ > δ = κ. In vitro, the compound acted as a potent (EC50 = 1.4 nM) κ-opioid agonist in the guinea pig ileum and a potent (EC50 = 0.2 nM) δ-opioid agonist in the mouse vas deferens but showed partial agonist activity at the rat cloned δ-opioid (40%) and human cloned κ-opioid (59%) receptors with very low efficacy at the rat cloned μ-opioid receptor (10%); findings consistent with its in vivo profile. BU48 is the first described compound that produces δ-opioid-mediated convulsions without any evidence of δ-opioid-mediated antinociception and will be a useful tool in investigations of the δ-opioid receptor.
Footnotes
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Send reprint requests to: Dr. J. R. Traynor, Department of Pharmacology, University of Michigan Medical School, 1301 MSRBIII, Ann Arbor, MI 48109-0632. E-mail:jtraynor{at}umich.edu
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↵1 This work was supported by U.S. Public Health Service Grants DA00254, DA07315, and GM07767. Portions of this work were presented in abstract form at the 1999 meeting of the College on Problems of Drug Dependence, Acapulco, Mexico, June 12–17 (Broom et al., 2000).
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↵2 Present address: Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201.
- Abbreviations:
- BW373U86
- (±)-[1(S*),2α,5β]-4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-hydroxyphenyl)methyl]-N,N-diethylbenzamide hydrochloride
- BNTX
- 7-benzylidenenaltrexone
- BU48
- N-cyclopropylmethyl-[7α,8α,2′,3′]cyclohexano-1′[S]-hydroxy-6,14-endo-ethenotetrahydronororipavine
- CI977
- 5R-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl-1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide
- C6δ
- C6 glioma cells transfected with the rat δ-receptor
- CHO
- Chinese hamster ovary
- EEG
- electroencephalographic
- CNS
- central nervous system
- CHO-hkor
- Chinese hamster ovary cells transfected with the human κ-receptor
- C6μ
- C6 glioma cells transfected with the rat μ-receptor
- DAMGO
- [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin
- DPDPE
- [d-Pen2,d-Pen5]-enkephalin
- GPI
- myenteric plexus-longitudinal muscle of the guinea pig ileum
- GTPγS
- guanosine-5′-O-(3-thio)triphosphate
- MVD
- mouse vas deferens
- norBNI
- norbinaltorphimine
- NTB
- naltriben
- NTI
- naltrindole
- SNC80
- (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide
- (−)-TAN-67
- 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino[2,3,3-g]isoquinoline
- U69593
- 5α,7α,8β-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneacetamide
- DMSO
- dimethyl sulfoxide
- Received January 14, 2000.
- Accepted May 25, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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