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SUVN-L1101142, A MUSCARINIC M4 POSITIVE ALLOSTERIC MODULATOR (M4 PAM) FOR THE TREATMENT OF PSYCHOSIS-RELATED DISORDERS AND CONDITION

Venkatesh Goura — Mayur Kumbhare1, Rajesh Babu Medapati1, Kumar Bojja1, Aamer Shaikh1, Rajesh kumar Badange1, Ankit Das1, Naga Sai Soma Chandra Sekhar Guduru1, Keerthi Sai Bitra1, Mary Praveena Nissankarao1, Hima Bindhu Bobbili1, Anindita Jana1, Sunitaben Gayakvad1, Sushant Thoke1, Ramakrishna Nirogi1 1Suven Life Sciences

2026 ASCP Annual Meeting

The muscarinic M4 receptor subtype shows the highest expression in brain regions such as the hippocampus, striatum, and prefrontal cortex, which are implicated in psychosis. Preclinical and clinical evidence suggests that hyperactive dopamine signaling in the striatum is associated with psychotic symptoms. Activation of the cholinergic system through the muscarinic M4 receptor can robustly modulate striatal dopamine signaling, thereby alleviating psychotic symptoms. Muscarinic M4 receptor positive allosteric modulators (M4 PAMs), which target the allosteric site rather than the orthosteric site of the receptor, have a better safety profile. In this context, we studied the safety and pharmacodynamic properties of an M4 PAM, SUVN L1101142. The effect of SUVN-L1101142 on the allosteric site of the muscarinic M4 and M2 receptors was characterized using the GloSensor cAMP assay, and on other muscarinic receptor subtypes (M1, M3, and M5) using the CRE-Luc reporter gene assay. The receptor occupancy of SUVN-L1101142 was evaluated in rats. The antipsychotic effects of SUVN-L1101142 were assessed in amphetamine-evoked hyperlocomotion and prepulse inhibition (PPI) deficits, and in a 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitch model in rats. To determine whether the effect observed in the DOI-induced head-twitch test was attributable to M4 receptor activity, the assay was conducted in the presence of an M4 antagonist. The social recognition task was used to evaluate procognitive properties. The likelihood of SUVN-L1101142 eliciting motor side effects was systematically investigated as part of a safety assessment to rule out potential adverse effects on the motor system. A preliminary toxicity study of SUVN-L1101142 was conducted in rats. SUVN-L1101142 was found to be a potent and selective M4 PAM with very high selectivity over other muscarinic receptor subtypes. SUVN-L1101142 attenuated amphetamine-evoked hyperlocomotion and PPI deficits, and DOI-induced head twitch. The efficacy observed with SUVN-L1101142 was attenuated by an M4 receptor antagonist, indicating that the observed efficacy was mediated through M4 receptors. SUVN-L1101142 reversed time delay induced memory deficits in a social recognition task in rats. There was no propensity to induce motor side effects at the tested doses. The observation from the behavioral assays correlated well with the receptor occupancy at the allosteric site of muscarinic M4 receptors. Preliminary toxicity studies in rats did not show any concerns for further development. SUVN-L1101142 has the potential to be a new therapeutic option for the treatment of psychosisrelated disorders and condition.