Pharmacological Characterization of the Muscarinic Agonist (3R,4R)-3-(3-Hexylsulfanyl-pyrazin-2-yloxy)-1-aza- bicyclo[2.2.1]heptane (WAY-132983) in in Vitro and in Vivo Models of Chronic Pain

Here, we have investigated the in vitro pharmacology of a muscarinic agonist, (3R,4R)-3-(3-hexylsulfanyl-pyrazin-2-yloxy)-1-aza-bicyclo[2.2.1]heptane (WAY-132983), and we demonstrated its activity in several models of pain. WAY-132983 had a similar affinity for the five muscarinic re-ceptors (9.4–29.0 nM); however, in calcium mobilization stud-ies it demonstrated moderate selectivity for M1 (IC50 6.6 nM; Emax 65 % of 10 M carbachol-stimulation) over the M3 (IC50 23 nM; Emax 41%) and M5 receptors (IC50 300 nM; Emax 18%). WAY-132983 also activated the M4 receptor, fully inhibiting forskolin-induced increase in cAMP levels (IC50 10.5 nM); at the M2 receptor its potency was reduced by 5-fold (IC50 49.8 nM). In vivo, WAY-132983 demonstrated good systemic bioavailability and high brain penetration (20-fol