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Research ArticleNEUROPHARMACOLOGY

BU48: A Novel Buprenorphine Analog That Exhibits δ-Opioid-Mediated Convulsions but Not δ-Opioid-Mediated Antinociception in Mice

Daniel C. Broom, Li Guo, Andrew Coop, Stephen M. Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 1195-1200;
Daniel C. Broom
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Li Guo
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Andrew Coop
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Stephen M. Husbands
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John W. Lewis
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James H. Woods
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John R. Traynor
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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

  • 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

  • ↵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).

  • ↵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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Journal of Pharmacology and Experimental Therapeutics: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
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Research ArticleNEUROPHARMACOLOGY

BU48: A Novel Buprenorphine Analog That Exhibits δ-Opioid-Mediated Convulsions but Not δ-Opioid-Mediated Antinociception in Mice

Daniel C. Broom, Li Guo, Andrew Coop, Stephen M. Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1195-1200;

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Research ArticleNEUROPHARMACOLOGY

BU48: A Novel Buprenorphine Analog That Exhibits δ-Opioid-Mediated Convulsions but Not δ-Opioid-Mediated Antinociception in Mice

Daniel C. Broom, Li Guo, Andrew Coop, Stephen M. Husbands, John W. Lewis, James H. Woods and John R. Traynor
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1195-1200;
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