VU0467319 (VU319) is a potent, selective and CNS penetrant M1 mAChR positive allosteric modulator (PAM) with EC50 of 492 nM, with minimal M1 agonism (EC50 > 30 uM).
VU0467319 (VU319) potentiates M1 in all three species: rat (M1 EC50 = 398 nM, 81.3 ± 11.3% ACh Max), mouse (M1 EC50 = 728 nM, 55.9 ± 5.6% ACh Max) and cyno (M1 EC50 = 374 nM, 57.8% ACh max).
VU0467319 (VU319) is ineffective in shifting ACh affinity at rat M2, M3, M4 or M5 receptors.
VU0467319 (VU319) potentiates the recruitment of β-arrestin2 to the human M1 receptor in a concentration dependent manner (EC50 = 890 nM, 72% max).
VU0467319 (VU319) also potentiates the response of oxotremorine-M (M1 EC50 = 400 nM, 59% ACh Max, M2–5 EC50 > 30 μM), but was ineffective at potentiating xanomeline, clozapine or N-desmethylclozapine (NDMC).
VU0467319 (VU319) demonstrated the feasibility of achieving selective targeting of central M1 muscarinic receptors without eliciting cholinergic AEs that have plagued other drugs targeting CNS cholinergic neurotransmission.