| Reference | 1. ACS Chem Neurosci. 2017 Mar 15;8(3):435-443. doi: 10.1021/acschemneuro.7b00001.
Epub 2017 Feb 13. <br />
Classics in Chemical Neuroscience: Xanomeline. <br />
Bender AM(1), Jones CK(1)(2), Lindsley CW(1)(2)(3). <br />
Author information: <br />
(1)Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University
School of Medicine , Nashville, Tennessee 37232, United States.
(2)Department of Pharmacology, Vanderbilt University School of Medicine ,
Nashville, Tennessee 37232, United States.
(3)Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt
University , Nashville, Tennessee 37232, United States. <br />
Xanomeline (1) is an orthosteric muscarinic acetylcholine receptor (mAChR)
agonist, often referred to as M1/M4-preferring, that received widespread
attention for its clinical efficacy in schizophrenia and Alzheimer/’s disease (AD)
patients. Despite the compound/’s promising initial clinical results,
dose-limiting side effects limited further clinical development. While
xanomeline, and related orthosteric muscarinic agonists, have yet to receive
approval from the FDA for the treatment of these CNS disorders, interest in the
compound/’s unique M1/M4-preferring mechanism of action is ongoing in the field of
chemical neuroscience. Specifically, the promising cognitive and behavioral
effects of xanomeline in both schizophrenia and AD have spurred a renewed
interest in the development of safer muscarinic ligands with improved subtype
selectivity for either M1 or M4. This Review will address xanomeline/’s overall
importance in the field of neuroscience, with a specific focus on its chemical
structure and synthesis, pharmacology, drug metabolism and pharmacokinetics
(DMPK), and adverse effects. <br />
2. CNS Drug Rev. 2003 Summer;9(2):159-86. <br />
Xanomeline and the antipsychotic potential of muscarinic receptor subtype
selective agonists. <br />
Mirza NR(1), Peters D, Sparks RG. <br />
Author information: <br />
(1)Department of Pharmacology, NeuroSearch A/S, 93 Pederstrupvej, Ballerup,
Denmark. [email protected] <br />
Binding studies initially suggested that the muscarinic agonist, xanomeline, was
a subtype selective muscarinic M(1) receptor agonist, and a potential new
treatment for Alzheimer/’s disease. However, later in vitro and in vivo functional
studies suggest that this compound is probably better described as a subtype
selective M(1)/M(4) muscarinic receptor agonist. This subtype selectivity profile
has been claimed to explain the limited classical cholinomimetic side effects,
particularly gastrointestinal, seen with xanomeline in animals. However, in both
healthy volunteers and Alzheimer/’s patients many of these side effects have been
reported for xanomeline and in the patient population this led to a >50%
discontinuation rate. Clearly, the preclinical studies have not been able to
predict this adverse profile of xanomeline, and this suggests that either
xanomeline is not as subtype selective as predicted from preclinical research or
that there are differences between humans and animals with regard to muscarinic
receptors. Nevertheless, in Alzheimer/’s patients xanomeline dose-dependently
improves aspects of behavioral disturbance and social behavior including a
reduction in hallucinations, agitation, delusions, vocal outbursts and
suspiciousness. The effects on cognition are not as robust and mainly seen at the
highest doses tested. These effects in Alzheimer/’s patients have given impetus to
the suggestion that muscarinic agonists have potential antipsychotic effects. The
current review assesses the antipsychotic profile of xanomeline within the
framework of the limited clinical studies with cholinergic agents in man, and the
preclinical research on xanomeline using various models commonly used for the
assessment of new antipsychotic drugs. In general, xanomeline has an
antipsychotic-like profile in various dopamine models of psychosis and this
agrees with the known interactions between the cholinergic and dopaminergic
systems in the brain. Moreover, current data suggests that the actions of
xanomeline at the M(4) muscarinic receptor subtype might mediate its
antidopaminergic effects. Particularly intriguing are studies showing that
xanomeline, even after acute administration, selectively inhibits the firing of
mesolimbic dopamine cells relative to dopamine cell bodies projecting to the
striatum. This data suggest that xanomeline would have a faster onset of action
compared to current antipsychotics and would not induce extrapyramidal side
effects. The preclinical data on the whole are promising for an
antipsychotic-like profile. If in a new formulation (i.e., transdermal)
xanomeline has less adverse effects, this drug may be valuable in the treatment
of patients with psychosis. <br />
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