| Reference | 1. CNS Drug Rev. 2004 Spring;10(1):1-22.
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Review of the pharmacological and clinical profile of rimcazole.
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Gilmore DL(1), Liu Y, Matsumoto RR.
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Author information: <br>
(1)Department of Pharmaceutical Sciences, University of Oklahoma Health Sciences
Center, P. O. Box 26901, Oklahoma City, OK 73190, USA.
<br>
Rimcazole is a carbazole derivative that acts in part as a sigma receptor
antagonist. Wellcome Research Laboratories introduced this compound during the
1980s when it was hypothesized to be a novel antipsychotic with an improved side
effect profile. However, subsequent clinical trials demonstrated that rimcazole
lacked efficacy in schizophrenic patients and it is now primarily used as an
experimental tool. In addition to its actions as a sigma receptor antagonist,
rimcazole also has high affinity for dopamine transporters, and in recent years
it has served as a lead compound for the development of novel dopamine
transporter ligands. Although rimcazole cannot be considered a selective ligand
for sigma receptors, the recent development of other selective agonists and
antagonists for sigma receptors have aided in clarifying the involvement of these
receptors in the actions of rimcazole. Many of the physiological and behavioral
effects of rimcazole can in fact be ascribed to its action as a sigma receptor
antagonist, although there are exceptions. Rimcazole is likely to have a
continued role in elucidating sigma receptor function in either in vitro or in
vivo systems where sigma receptor-mediated effects can be studied independently
of the influence of dopamine and serotonin transporters.
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2. Med Res Rev. 2002 Sep;22(5):429-64.
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Probes for the dopamine transporter: new leads toward a cocaine-abuse
therapeutic–A focus on analogues of benztropine and rimcazole.
<br>
Newman AH(1), Kulkarni S.
<br>
Author information: <br>
(1)Medicinal Chemistry Section, National Institute on Drug Abuse–Intramural
Research Program, National Institutes of Health, 5500 Nathan Shock Drive,
Baltimore, Maryland 21224, USA. [email protected]
<br>
In an attempt to discover a cocaine-abuse pharmacotherapeutic, extensive
investigation has been directed toward elucidating the molecular mechanisms
underlying the reinforcing effects of this psychostimulant drug. The results of
these studies have been consistent with the inhibition of dopamine uptake, at the
dopamine transporter (DAT), which results in a rapid and excessive accumulation
of extracellular dopamine in the synapse as being the mechanism primarily
responsible for the locomotor stimulant actions of cocaine. Nevertheless,
investigation of the serotonin (SERT) and norepinephrine (NET) transporters, as
well as other receptor systems, with which cocaine either directly or indirectly
interacts, has suggested that the DAT is not solely responsible for the
reinforcing effects of cocaine. In an attempt to further elucidate the roles of
these systems in the reinforcing effects of cocaine, selective molecular probes,
in the form of drug molecules, have been designed, synthesized, and
characterized. Many of these compounds bind potently and selectively to the DAT,
block dopamine reuptake, and are behaviorally cocaine-like in animal models of
psychostimulant abuse. However, there have been exceptions noted in several
classes of dopamine uptake inhibitors that demonstrate behavioral profiles that
are distinctive from cocaine. Structure-activity relationships between chemically
diverse dopamine uptake inhibitors have suggested that different binding
interactions, at the molecular level on the DAT, as well as divergent actions at
the other monoamine transporters may be related to the differing pharmacological
actions of these compounds, in vivo. These studies suggest that novel dopamine
uptake inhibitors, which are structurally and pharmacologically distinct from
cocaine, may be developed as potential cocaine-abuse therapeutics.
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