(L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats.
Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. The anti-allodynic effects of gabapentin and pregabalin, along with three other compounds--(L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA)--discovered to be potent alpha2delta ligands, were tested in the rat spinal nerve ligation model of neuropathic pain. Gabapentin (Ki = 120 nM), pregabalin (180 nM) and (L)-phenylglycine (180 nM) were shown to be anti-allodynic, with respective ED50 values of 230, 90 and 80 micromol/kg (p.o.). (L)-Phenylglycine was as potent as pregabalin and equi-efficacious in reversing mechanical allodynia. In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.
Lynch
James J
JJ
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. james.j.lynch@abbott.com
Honore
Prisca
P
Anderson
David J
DJ
Bunnelle
William H
WH
Mortell
Kathleen H
KH
Zhong
Chengmin
C
Wade
Carrie L
CL
Zhu
Chang Z
CZ
Xu
Hongyu
H
Marsh
Kennan C
KC
Lee
Chih-Hung
CH
Jarvis
Michael F
MF
Gopalakrishnan
Murali
M
D000700:Analgesics / Q000008:administration & dosage; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism*; D020746:Calcium Channels, L-Type; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006941:Hyperesthesia / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D009437:Neuralgia / Q000378:metabolism* / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D000700:Analgesics; C486060:Cacna2d1 protein, rat; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; C008852:2-phenylglycine; D005998:Glycine