Electrophysiological and in vivo characterization of A-317567, a novel blocker of acid sensing ion channels.
Acid Sensing Ion Channels (ASICs) are a group of sodium-selective ion channels that are activated by low extracellular pH. The role of ASIC in disease states remains unclear partly due to the lack of selective pharmacological agents. In this report, we describe the effects of A-317567, a novel non-amiloride blocker, on three distinct types of native ASIC currents evoked in acutely dissociated adult rat dorsal root ganglion (DRG) neurons. A-317567 produced concentration-dependent inhibition of all pH 4.5-evoked ASIC currents with an IC50 ranging between 2 and 30muM, depending upon the type of ASIC current activated. Unlike amiloride, A-317567 equipotently blocked the sustained phase of ASIC3-like current, a biphasic current akin to cloned ASIC3, which is predominant in DRG. When evaluated in the rat Complete Freud's Adjuvant (CFA)-induced inflammatory thermal hyperalgesia model, A-317567 was fully efficacious at a dose 10-fold lower than amiloride. A-317567 was also potent and fully efficacious when tested in the skin incision model of post-operative pain. A-317567 was entirely devoid of any diuresis or natriuresis activity and showed minimal brain penetration. In summary, A-317567 is the first reported small molecule non-amiloride blocker of ASIC that is peripherally active and is more potent than amiloride in vitro and in vivo pain models. The discovery of A-317567 will greatly help to enhance our understanding of the physiological and pathophysiological role of ASICs.
Dubé
G R
GR
Abbott Laboratories, Neuroscience Research, Building AP9A-Dept. R4ND,Abbott Park, IL 60064-6118, USA. gilles.dube@abbott.com
Lehto
Sonya G
SG
Breese
Nicole M
NM
Baker
Scott J
SJ
Wang
Xueqing
X
Matulenko
Mark A
MA
Honoré
Prisca
P
Stewart
Andrew O
AO
Moreland
Robert B
RB
Brioni
Jorge D
JD
D062565:Acid Sensing Ion Channels; D000143:Acids / Q000494:pharmacology*; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002452:Cell Count / Q000379:methods; D048429:Cell Size; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005620:Freund's Adjuvant; D005727:Ganglia, Spinal / Q000166:cytology*; D006863:Hydrogen-Ion Concentration; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007546:Isoquinolines / Q000494:pharmacology / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008565:Membrane Proteins / Q000145:classification / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology / Q000627:therapeutic use; D009419:Nerve Tissue Proteins / Q000145:classification / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects*; D010147:Pain Measurement / Q000379:methods; D017288:Pain Threshold / Q000187:drug effects; D010149:Postoperative Pain / Q000139:chemically induced / Q000178:diet therapy; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000145:classification / Q000187:drug effects*
C506640:A-317567; C568269:ASIC3 protein, rat; D062565:Acid Sensing Ion Channels; D000143:Acids; D007546:Isoquinolines; D008565:Membrane Proteins; D009281:Naphthalenes; D009419:Nerve Tissue Proteins; D015222:Sodium Channels; D000584:Amiloride; D005620:Freund's Adjuvant