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 receptors (9.4-29.0 nM); however, in
calcium mobilization studies it demonstrated moderate selectivity for M(1) (IC(50) = 6.6 nM; E(max) = 65% of 10 muM
carbachol-stimulation) over the M(3) (IC(50) = 23 nM; E(max) = 41%) and M(5) receptors (IC(50) = 300 nM; E(max) = 18%).
WAY-132983 also activated the M(4) receptor, fully inhibiting
forskolin-induced increase in cAMP levels (IC(50) = 10.5 nM); at the M(2) receptor its potency was reduced by 5-fold (IC(50) = 49.8 nM). In vivo,
WAY-132983 demonstrated good systemic bioavailability and high brain penetration (>20-fold over plasma levels). In addition, WAY-1329823 produced potent and efficacious antihyperalgesic and antiallodynic effects in rodent models of chemical
irritant, chronic inflammatory, neuropathic, and incisional
pain. It is noteworthy that efficacy in these models was observed at doses that did not produce
analgesia or
ataxia. Furthermore, a series of antagonist studies demonstrated that the in vivo activity of
WAY-132983 is mediated through activation of
muscarinic receptors primarily through the M(4) receptor. The data presented herein suggest that
muscarinic agonists, such as
WAY-132983, may have a broad therapeutic efficacy for the treatment of
pain.