The Muscarinic M1/M4 Receptor Agonist Xanomeline Exhibits Antipsychotic-Like Activity in Cebus apella Monkeys

Abstract

Xanomeline is a muscarinic M 1 /M 4 preferring receptor agonist with little or no affinity for dopamine receptors. The compound reduces psychotic-like symptoms in patients with Alzheimer's disease and exhibits an antipsychotic-like profile in rodents without inducing extrapyramidal side effects (EPS) at therapeutically relevant doses. In the present study, we examined whether the xanomeline-induced functional dopamine antagonism found in rodent studies could also be observed in nonhuman primates. In addition, we studied whether the lack of EPS observed in rodents also applies to primates. To this end, we investigated the effects of xanomeline on the behavior induced by D-amphetamine and (À)-apomorphine in drug-naive Cebus apella monkeys. Antipsychotic compounds antagonize amphetamine-induced motor unrest and stereotypies in this species. Xanomeline inhibited D-amphetamine-induced motor unrest, stereotypies and arousal as well as apomorphine-induced stereotypies and arousal in drug-naive Cebus apella monkeys. Xanomeline did not induce EPS but vomiting occurred in some monkeys at high doses, in accordance with emetic events observed in Alzheimer patients following xanomeline administration. Even when xanomeline was tested in EPS-sensitized Cebus apella monkeys, EPS were not observed at the dose range of xanomeline used in the D-amphetamine-apomorphine combination study (0.5-3 mg/kg). However, when xanomeline was tested at 4 mg/kg, moderate dystonia was seen in two out of three monkeys. It is concluded that xanomeline inhibits Damphetamine-and (À)-apomorphine-induced behavior in Cebus apella monkeys at doses that do not cause EPS. These data further substantiate that muscarinic receptor agonists may be useful in the pharmacological treatment of psychosis.

Towards a muscarinic hypothesis of schizophrenia

“…[140][141][142] Similar to traditional antipsychotic compounds, treatment with xanomeline inhibited the behavioral and motor effects of amphetamine and apomorphine in monkeys. 143 Recent data suggest that xanomeline is also an antagonist at the M 5 receptor. 144 As muscarinic neurons carrying M 5 receptors have synaptic contact with dopaminergic neurons in the brainstem, the functional antagonism of xanomeline at M 5 receptors may offer an additional modulatory pathway on dopaminergic cell-firing.…”

Antipsychotic Drug-Like Effects of the Selective M4 Muscarinic Acetylcholine Receptor Positive Allosteric Modulator VU0152100

“…Although encouraging, there have been only two clinical studies with xanomeline published to date indicating that these initial findings should be viewed with caution until further clinical validation is reported. Xanomeline also showed robust efficacy in animal models predictive of APDlike activity comparable to the effects observed with the atypical antipsychotic clozapine, including reversal of psychostimulant-induced hyperlocomotion and disruption of prepulse inhibition (PPI) of the acoustic startle reflex (Andersen et al, 2003;Jones et al, 2005;Perry et al, 2001;Shannon et al, 2000;Stanhope et al, 2001). Unfortunately, xanomeline like other muscarinic agonists ultimately failed in clinical development due to a lack of complete receptor subtype selectivity resulting in adverse side effects associated with non-selective activation of peripheral M 2 and M 3 mAChRs (Bodick et al, 1997;Shekhar et al, 2008).…”

Wash-Resistantly Bound Xanomeline Inhibits Acetylcholine Release by Persistent Activation of Presynaptic M2and M4Muscarinic Receptors in Rat Brain

“…However, original clinical trials revealed frequent peripheral side effects that were not consistent with M 1 selectivity and led to interruption of testing (Mirza et al, 2003). More recent behavioral studies in rodents, primates, and clinical studies have pointed to potential profitable antipsychotic effects that are ascribed to the M 1 /M 4 agonistic profile of the drug (Bymaster et al, 2002;Andersen et al, 2003).…”