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.
Sullivan
Nicole R
NR
Neuroscience Discovery Research, Wyeth Research, CN8000, Princeton, NJ 08543, USA. sullivan@wyeth.com
Leventhal
Liza
L
Harrison
James
J
Smith
Valerie A
VA
Cummons
Terri A
TA
Spangler
Taylor B
TB
Sun
Shaiu-Ching
SC
Lu
Peimin
P
Uveges
Albert J
AJ
Strassle
Brian W
BW
Piesla
Michael J
MJ
Ramdass
Rana
R
Barry
Alena
A
Schantz
Jonathan
J
Adams
William
W
Whiteside
Garth T
GT
Adedoyin
Adedayo
A
Jones
Philip G
PG
D000818:Animals; D001682:Biological Availability; D001952:Bridged-Ring Compounds / Q000493:pharmacokinetics* / Q000494:pharmacology; D002908:Chronic Disease; D004195:Disease Models, Animal; D007249:Inflammation; D020128:Inhibitory Concentration 50; D018721:Muscarinic Agonists / Q000494:pharmacology*; D010146:Pain / Q000517:prevention & control*; D011719:Pyrazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic
D001952:Bridged-Ring Compounds; D018721:Muscarinic Agonists; D011719:Pyrazines; D011976:Receptors, Muscarinic; C121282:WAY 132983