BU48: A Novel Buprenorphine Analog That Exhibits -Opioid-
Mediated Convulsions but Not -Opioid-Mediated
Antinociception in Mice
1
DANIEL C. BROOM, LI GUO, ANDREW COOP,
2
STEPHEN M. HUSBANDS, JOHN W. LEWIS, JAMES H. WOODS, and
JOHN R. TRAYNOR
Departments of Pharmacology (D.C.B., J.H.W., J.R.T.) and Psychology (J.H.W.), University of Michigan Medical School, Ann Arbor, Michigan;
Department of Chemistry, University of Bristol, Bristol, United Kingdom (A.C., S.M.H., J.W.L.); and Department of Chemistry, Loughborough
University, Loughborough, United Kingdom (L.G., J.R.T.)
Accepted for publication May 25, 2000 This paper is available online at http://www.jpet.org
ABSTRACT
N-Cyclopropylmethyl-[7,8,2' ,3' ]-cyclohexano-1' [ S]-hy-
droxy-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 cata-
lepsy characteristic of BW373U86 and other nonpeptidic -re-
ceptor agonists. BU48-induced convulsions were sensitive to
antagonism by naltrindole (10 mg/kg s.c.) and were also pre-
vented by administration of the putative
1
antagonist 7-ben-
zylidenenaltrexone and the putative
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
-opioid antagonist norbinaltorphimine (32 mg/kg s.c.) but not
by the -opioid antagonist naltrindole (10 mg/kg s.c.). BU48 (10
mg/kg s.c.) acted as a -antagonist in this assay. In mouse
brain homogenates, BU48 had high (nanomolar) binding affinity
for all three opioid receptors in the order = . In vitro, the
compound acted as a potent (EC
50
= 1.4 nM) -opioid agonist
in the guinea pig ileum and a potent (EC
50
= 0.2 nM) -opioid
agonist in the mouse vas deferens but showed partial agonist
activity at the rat cloned -opioid (40%) and human cloned
-opioid (59%) receptors with very low efficacy at the rat cloned
-opioid receptor (10%); findings consistent with its in vivo
profile. BU48 is the first described compound that produces
-opioid-mediated convulsions without any evidence of -opi-
oid-mediated antinociception and will be a useful tool in inves-
tigations of the -opioid receptor.
In the search for narcotic analgesic agents without the
unwanted complications of -opioid receptor agonists such as
morphine, research has focused on the -opioid receptor as a
target for antinociceptive agents. This has culminated in the
suggestion of -opioid receptor subtypes (for review, see
Traynor and Elliot, 1993) and the discovery of the nonpeptide
-opioid agonist BW373U86 and related compounds (e.g.,
Chang et al., 1993). BW373U86 produces antinociception
without any apparent respiratory complications (Negus et
al., 1994), although studies in mice showed a consistent and
reproducible dose-dependent convulsive effect associated
with BW373U86 administration (Comer et al., 1993). The
convulsive activity of this compound has also been noted in
squirrel monkeys (Dykstra et al., 1993; Pakarinen et al.,
1995) and rhesus monkeys (Hong et al., 1998).
The synthesis of SNC80, the methyl ether of the (+)-isomer
of BW373U86 (Calderon et al., 1994), produced a compound
more potent than BW373U86 as an antinociceptive agent.
Received for publication January 14, 2000.
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*),2,5]-4-[[2,5-dimethyl-4-(2-propenyl)-1-piperazinyl](3-hydroxyphenyl)methyl]-N,N-diethylbenzamide
hydrochloride; BNTX, 7-benzylidenenaltrexone; BU48, N-cyclopropylmethyl-[7,8,2',3']cyclohexano-1'[S]-hydroxy-6,14-endo-ethenotetrahy-
dronororipavine; CI977, 5R-(5,7,8)-N-methyl-N-[7-(1-pyrrolidinyl-1-oxaspiro[4,5]dec-8-yl]-4-benzofuranacetamide; C6, C6 glioma cells
transfected with the rat -receptor; CHO, Chinese hamster ovary; EEG, electroencephalographic; CNS, central nervous system; CHO-hkor,
Chinese hamster ovary cells transfected with the human -receptor; C6, C6 glioma cells transfected with the rat -receptor; DAMGO,
[D-Ala
2
,N-Me-Phe
4
,Gly
5
-ol]-enkephalin; DPDPE, [D-Pen
2
,D-Pen
5
]-enkephalin; GPI, myenteric plexus-longitudinal muscle of the guinea pig ileum;
GTPS, guanosine-5'-O-(3-thio)triphosphate; MVD, mouse vas deferens; norBNI, norbinaltorphimine; NTB, naltriben; NTI, naltrindole; SNC80,
(+)-4-[(R)--((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide; (-)-TAN-67, 2-methyl-4a-(3-hydroxyphen-
yl)-1,2,3,4,4a,5,12,12a-octahydroquinolino[2,3,3-g]isoquinoline; U69593, 5,7,8-(+)-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4,5]dec-8-yl]benzeneac-
etamide; DMSO, dimethyl sulfoxide.
0022-3565/00/2943-1195$03.00/0
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