Abstract
We previously reported the small organic N-type calcium channel blocker NP078585 that while efficacious in animal models for pain, exhibited modest L-type calcium channel selectivity and substantial off-target inhibition against the hERG potassium channel. Structure-activity studies to optimize NP078585 preclinical properties resulted in compound 16, which maintained high potency for N-type calcium channel blockade, and possessed excellent selectivity over the hERG (~120-fold) and L-type (~3600-fold) channels. Compound 16 shows significant anti-hyperalgesic activity in the spinal nerve ligation model of neuropathic pain and is also efficacious in the rat formalin model of inflammatory pain.
Copyright © 2012 Elsevier Ltd. All rights reserved.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Analgesics / chemical synthesis*
-
Analgesics / pharmacology
-
Animals
-
Calcium Channel Blockers / chemical synthesis*
-
Calcium Channel Blockers / pharmacology
-
Calcium Channels, L-Type / metabolism
-
Calcium Channels, N-Type / metabolism*
-
Disease Models, Animal
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels / metabolism
-
Hyperalgesia / drug therapy*
-
Hyperalgesia / metabolism
-
Neuralgia / drug therapy*
-
Neuralgia / metabolism
-
Piperazines / chemical synthesis*
-
Piperazines / pharmacology
-
Rats
-
Rats, Sprague-Dawley
-
Spinal Nerves / drug effects*
-
Spinal Nerves / metabolism
-
Structure-Activity Relationship
Substances
-
1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine
-
Analgesics
-
Calcium Channel Blockers
-
Calcium Channels, L-Type
-
Calcium Channels, N-Type
-
ERG1 Potassium Channel
-
Ether-A-Go-Go Potassium Channels
-
Piperazines