Analgesic effects of a substituted N-triazole oxindole (TROX-1), a state-dependent, voltage-gated calcium channel 2 blocker.
Voltage-gated calcium channel (Ca(v))2.2 (N-type calcium channels) are key components in nociceptive transmission pathways. Ziconotide, a state-independent peptide inhibitor of Ca(v)2.2 channels, is efficacious in treating refractory pain but exhibits a narrow therapeutic window and must be administered intrathecally. We have discovered an N-triazole oxindole, (3R)-5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one (TROX-1), as a small-molecule, state-dependent blocker of Ca(v)2 channels, and we investigated the therapeutic advantages of this compound for analgesia. TROX-1 preferentially inhibited potassium-triggered calcium influx through recombinant Ca(v)2.2 channels under depolarized conditions (IC(50) = 0.27 microM) compared with hyperpolarized conditions (IC(50) > 20 microM). In rat dorsal root ganglion (DRG) neurons, TROX-1 inhibited omega-conotoxin GVIA-sensitive calcium currents (Ca(v)2.2 channel currents), with greater potency under depolarized conditions (IC(50) = 0.4 microM) than under hyperpolarized conditions (IC(50) = 2.6 microM), indicating state-dependent Ca(v)2.2 channel block of native as well as recombinant channels. TROX-1 fully blocked calcium influx mediated by a mixture of Ca(v)2 channels in calcium imaging experiments in rat DRG neurons, indicating additional block of all Ca(v)2 family channels. TROX-1 reversed inflammatory-induced hyperalgesia with maximal effects equivalent to nonsteroidal anti-inflammatory drugs, and it reversed nerve injury-induced allodynia to the same extent as pregabalin and duloxetine. In contrast, no significant reversal of hyperalgesia was observed in Ca(v)2.2 gene-deleted mice. Mild impairment of motor function in the Rotarod test and cardiovascular functions were observed at 20- to 40-fold higher plasma concentrations than required for analgesic activities. TROX-1 demonstrates that an orally available state-dependent Ca(v)2 channel blocker may achieve a therapeutic window suitable for the treatment of chronic pain.
Abbadie
Catherine
C
Department of Pharmacology,Merck Research Laboratories, Rahway, New Jersey 07065, USA.
McManus
Owen B
OB
Sun
Shu-Yu
SY
Bugianesi
Randal M
RM
Dai
Ge
G
Haedo
Rodolfo J
RJ
Herrington
James B
JB
Kaczorowski
Gregory J
GJ
Smith
McHardy M
MM
Swensen
Andrew M
AM
Warren
Vivien A
VA
Williams
Brande
B
Arneric
Stephen P
SP
Eduljee
Cyrus
C
Snutch
Terrance P
TP
Tringham
Elizabeth W
EW
Jochnowitz
Nina
N
Liang
Annie
A
Euan MacIntyre
D
D
McGowan
Erin
E
Mistry
Shruti
S
White
Valerie V
VV
Hoyt
Scott B
SB
London
Clare
C
Lyons
Kathryn A
KA
Bunting
Patricia B
PB
Volksdorf
Sylvia
S
Duffy
Joseph L
JL
D000700:Analgesics / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D017704:Baroreflex / Q000187:drug effects; D001682:Biological Availability; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D020864:Calcium Channels, N-Type / Q000235:genetics / Q000502:physiology*; D020908:Calcium Channels, R-Type / Q000502:physiology; D027682:Cation Transport Proteins / Q000502:physiology; D002460:Cell Line; D004285:Dogs; D005727:Ganglia, Spinal / Q000187:drug effects / Q000502:physiology; D006930:Hyperalgesia / Q000188:drug therapy; D007024:Hypotension, Orthostatic / Q000139:chemically induced; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*
C551468:5-(3-chloro-4-fluorophenyl)-3-methyl-3-(pyrimidin-5-ylmethyl)-1-(1H-1,2,4-triazol-3-yl)-1,3-dihydro-2H-indol-2-one; D000700:Analgesics; C500963:Cacna1b protein, mouse; C503279:Cacna1b protein, rat; C498917:Cacna1e protein, rat; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D020908:Calcium Channels, R-Type; D027682:Cation Transport Proteins; D007211:Indoles; D014230:Triazoles