Drug and Alcohol Dependence 64 (2001) 203–208
-carboline binding to imidazoline receptors
Stephen M. Husbands
a,
*, Richard A. Glennon
b
, Stephane Gorgerat
c
,
Rhianon Gough
d
, Robin Tyacke
d
, John Crosby
c
, David J. Nutt
d
, John W. Lewis
c
,
Alan L. Hudson
d
a
Department of Pharmacy and Pharmacology, Uniersity of Bath, Bath, BA27AY, UK
b
Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth Uniersity, Box 980540, Richmond, VA 23298, USA
c
School of Chemistry, Uniersity of Bristol, Bristol, BS81TS, UK
d
Psychopharmacology Unit, Uniersity of Bristol, Bristol, BS81TD, UK
Received 29 September 2000; accepted 24 January 2001
Abstract
A series of -carbolines were prepared and their affinities for imidazoline (I
1
and I
2
) sites evaluated. Selected compounds were
also examined at
2
-adrenoceptors. Some of the -carbolines were found to bind with high affinity to I
2
-sites and this affinity was
dependent on both the planarity of the molecule and the presence of the aryl ring substituents. Good I
1
-affinity was observed with
two of the compounds but none of the tested compounds bound to
2
-adrenoceptors. The hallucinogenic properties of
-carbolines have been linked to activity at 5-HT receptors, in particular 5-HT
2
, however, it is apparent from this study that many
of these compounds display substantially higher affinity for the imidazoline sites. This finding, and those showing modulation of
some behavioural effects of morphine by I
2
-ligands, suggests that imidazoline sites may be interesting new targets in drug abuse
research. © 2001 Elsevier Science Ireland Ltd. All rights reserved.
Keywords: -carbolines; Harmine; Harmaline; Hallucinogens; Imidazoline binding sites; SAR
www.elsevier.com/locate/drugalcdep
1. Introduction
While imidazoline binding sites have only recently
been discovered and their pharmacological role is still
being elucidated, there is a growing body of evidence to
suggest that they could be important therapeutic targets
for a number of conditions. It is now recognised that
the mammalian imidazoline binding sites can be divided
into two main subtypes (I
1
and I
2
), although evidence
exists for a further two (Eglen et al., 1998; Gothert et
al., 1999). The I
1
site has been proposed to mediate the
antihypertensive effects of rilmenidine (1)
®
and mox-
onidine (2)
®
(Fig. 1); however, there is debate over
whether this is a pure I
1
-mediated effect or whether it
involves additional
2
-adrenoceptor agonism (Eglen et
al., 1998). The lack of highly selective ligands for the I
1
site has hindered attempts to resolve this debate, be-
cause such ligands also display affinity for I
2
sites or
2
-adrenoceptors. In contrast, there are now a number
of ligands that are highly selective for the I
2
site over
both I
1
and the
2
-adrenoceptors. These include the
benzofuran 2-BFI (3), the quinoline BU224 (4) and the
isoquinoline BU226 (5) (Fig. 1) (Hudson et al., 1997,
1999a). The I
2
site has been implicated in a number of
neuropsychiatric conditions including depression, and
Alzheimer’s, Huntington’s and Parkinson’s diseases
(Garcia Sevilla et al., 1995; Reynolds et al., 1996; Sastre
and Garcia Sevilla, 1996; Lalies et al., 1998). There is
also mounting evidence that I
2
ligands can modulate
some of the behavioural effects of morphine and that
there exists a functional interaction between I
2
and
opioid receptors. For example, I
2
-selective ligands such
as 2-BFI enhance morphine-evoked supraspinal anti-
nociception in a dose dependent manner, an effect that
can be blocked by BU224 (Sanchez-Blazquez et al.,
2000). Additionally BU224 can reduce some of the
symptoms of morphine withdrawal in a rat model of
opiate dependence (Hudson et al., 1999a), potentially
opening up a new avenue in drug abuse research.
* Corresponding author. Tel.: +44-1225-826826 ext. 4997; fax:
+44-1225-826114.
E-mail address: s.m.husbands@bath.ac.uk (S.M. Husbands).
0376-8716/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved.
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