MK-7622 / Merck (MSD) - LARVOL DELTA

Investigating Drivers for M Muscarinic Acetylcholine Receptor-Mediated Adverse Events by M Positive Allosteric Modulators. (PubMed, FASEB J) - "Gα , Gα and b-arrestin 1/2 influence binding affinity and functional properties for both ACh and M PAMs. These transductors affect M PAMs with observed AEs more than the M PAM without AEs, VU0486846, and thus playing a potential role in driving AEs."

Adverse events • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Developmental Disorders • Epilepsy • Gastrointestinal Disorder • Psychiatry • Schizophrenia • ARRB1

T-495, a novel low cooperative M receptor positive allosteric modulator, improves memory deficits associated with cholinergic dysfunction and is characterized by low gastrointestinal side effect risk. (PubMed, Pharmacol Res Perspect) - "In fact, TAK-071, a novel M R PAM with low cooperativity (α-value of 199), improved scopolamine-induced cognitive deficits with a wider margin against GI side effects than a high cooperative M R PAM, T-662 (α-value of 1786), in rats. Here, we describe the pharmacological characteristics of a novel low cooperative M R PAM T-495 (α-value of 170), using the clinically tested higher cooperative M R PAM MK-7622 (α-value of 511) as a control...Additionally, in mice with reduced acetylcholine levels in the forebrain via overexpression of A53T α-synuclein (ie, a mouse model of dementia with Lewy bodies and Parkinson's disease with dementia), T-495, like donepezil, reversed the memory deficits in the contextual fear conditioning test and Y-maze task. Thus, low cooperative M R PAMs are promising agents for the treatment of memory deficits associated with cholinergic dysfunction."

Adverse events • Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Gastrointestinal Disorder • Lewy Body Disease • Movement Disorders • Parkinson's Disease

MK-7622: A First-in-Class M Positive Allosteric Modulator Development Candidate. (PubMed, ACS Med Chem Lett) - "Identification of ligands that selectively activate the M muscarinic signaling pathway has been sought for decades to treat a range of neurological and cognitive disorders. Herein, we describe the optimization efforts focused on addressing key physicochemical and safety properties, ultimately leading to the clinical candidate MK-7622, a highly selective positive allosteric modulator of the M muscarinic receptor that has entered Phase II studies in patients with Alzheimer's disease."

Journal • Alzheimer's Disease • Biosimilar • CNS Disorders

A novel M1 PAM VU0486846 exerts efficacy in cognition models without displaying agonist activity or cholinergic toxicity. (PubMed, ACS Chem Neurosci) - "However, highly potent M ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50s > 100 nM) and pure-PAM activity in native tissues display robust pro-cognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development."

Clinical • Journal

Preclinical to Human Translational Pharmacology of the Novel MPositive Allosteric Modulator MK-7622. (PubMed, J Pharmacol Exp Ther) - "Additionally, there were differences in the spectral power changes produced by MK-7622 in rhesus vs. human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in man for a selective M1 muscarinic receptor positive allosteric modulator."

Journal • Preclinical

Optimization of novel M1 PAMs for clinical development with enhanced efficacy while avoiding adverse effect liability for the treatment of Alzheimer’s disease (AAIC 2019) - "In addition, highly potent M1 agonist-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events. The VCNDD has developed highly potent, selective M1 PAMs with enhanced physiochemical and pharmacokinetic properties and clean safety profile, providing an unprecedented opportunity to evaluate the potential of selective potentiation of M1 as a novel treatment of symptoms associated with AD. As opposed to direct activation of M1, PAMs dramatically potentiate the response of the receptor to its endogenous ligand acetylcholine, offering high selectivity while maintaining normal spatiotemporal signaling patterns and avoiding adverse effects of overstimulation. Phase I clinical trials are currently being conducted with the M1 PAM clinical candidate VU319 under the direction of..."

Adverse events • Clinical