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 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.

A New Method to Collect Bile and Access the Duodenum in Conscious Dogs.

A novel, totally implantable catheter system that allows complete bile collection and duodenal access in conscious, freely moving dogs is described. Bile collection catheters remained patent for an average of 417 days (range, 711010 days) in eight animals which were used on study. Three animals have been used to validate the models complete collection of bile via biliary recovery of an intravenous dose of 14C-glycocholic acid, and in selected animals, parameters potentially indicative of liver damage (serum alanine aminotransferase, alkaline phosphatase, gamma glutamyltransferase, and total bilirubin levels) were within normal ranges for as many as 14 months after surgery. The eight study dogs have been used in a total of 29 studies, in which bile was successfully collected for 1248 h. The bile has been collected by using either a tethering system or a protected pouch arrangement. Compared to exteriorized catheter techniques, this system requires less maintenance and is better tolerated by the animals. The potential for a longer functional life span for individual animals, more normal liver enzymes, and the capability to selectively infuse towards the duodenum and flush the entire catheter and bile duct are other advantages of this model.