Drug Development.

Background: SUVN-I7016031 is a novel and selective positive allosteric modulator (PAM) of the M1 subtype of the muscarinic acetylcholine receptors (mAChRs). The proposed primary indication for SUVN-I7016031 is in the treatment of dementia such as Alzheimer's disease dementia (ADD) and Parkinson's disease dementia (PDD). In the current research, the pharmacological properties of SUVN-I7016031 in various types of dementia were investigated.

Method: SUVN-I7016301 was characterized using a calcium mobilization assay. The binding affinity towards the orthosteric M1 - M5 site was investigated. The effect of SUVN-I7016031 on neuronal spike rate in coronal hippocampal slice electrophysiology was studied in agonist and PAM modes of testing. The pharmacokinetic properties of SUVN-I7016031 were studied both in rodent and non-rodent species. The effect of SUVN-I7016031 on MK-801 induced memory deficits in rats using object recognition task (ORT) and on time-induced social memory deficits in rats using social recognition task (SRT) was studied. The efficacy of SUVN-I7016031 in a rat model of PDD was investigated. The effects of SUVN-I7016031 (10-60 mg/kg, p.o.) on inositol 1 phosphate (IP-1) levels were studied in rats.

Result: Functionally, SUVN-I7016031 was found to be a positive allosteric modulator at the M1 receptor with an allosteric potency EC of 355 nM. In hippocampal slice electrophysiology studies, the EC and EC values were ∼527 nM and ∼326 nM, respectively. No significant binding towards the orthosteric site at the muscarinic M1 to M5 receptor was observed. SUVN-I7016031 showed good oral bioavailability in rats, dogs, and monkeys. SUVN-I7016031 was found to have brain penetration properties with adequate free fraction. SUVN-I7016031 reversed delay-induced memory disruption in adult rats in a SRT and antagonized MK-801 induced memory disruption in ORT. SUVN-I7016031 was found to reverse haloperidol induced memory deficits, a rat model of PDD. Treatment with SUVN-I7016031 produced a significant increase in striatal inositol 1-phosphate (IP-1) levels in rats, providing in-vivo support for the activation of M1 mAChRs by SUVN-I7016031.

Conclusion: SUVN-I7016031 is a novel, potent, and selective M1-PAM that demonstrated pro-cognitive effects in animal models of PDD and ADD.