ABSTRACT
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.
Subject(s)
Analgesics/pharmacology , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/physiology , Indoles/pharmacology , Triazoles/pharmacology , Analgesics/adverse effects , Analgesics/pharmacokinetics , Animals , Baroreflex/drug effects , Biological Availability , Calcium Channel Blockers/adverse effects , Calcium Channel Blockers/pharmacokinetics , Calcium Channels, N-Type/genetics , Calcium Channels, R-Type/physiology , Cation Transport Proteins/physiology , Cell Line , Dogs , Ganglia, Spinal/drug effects , Ganglia, Spinal/physiology , Hyperalgesia/drug therapy , Hypotension, Orthostatic/chemically induced , Indoles/adverse effects , Indoles/pharmacokinetics , Male , Mice , Mice, Knockout , Neurons/drug effects , Neurons/physiology , Pain/drug therapy , Pain/etiology , Patch-Clamp Techniques , Rats , Rats, Sprague-Dawley , Triazoles/adverse effects , Triazoles/pharmacokineticsABSTRACT
The synthesis, SAR and binding affinities are described for cannabinoid-1 receptor (CB1R) specific inverse agonists based on pyridopyrimidine and heterotricyclic scaffolds. Food intake and pharmacokinetic evaluation of several of these compounds indicate that they are effective orally active modulators of CB1R.
Subject(s)
Cannabinoid Receptor Agonists , Obesity/drug therapy , Pyrimidines/chemistry , Administration, Oral , Animals , Cannabinoids/chemistry , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Protein Structure, Tertiary , Rats , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB2/agonists , Structure-Activity RelationshipABSTRACT
A series of 3-amino-1,5-benzodiazepinones were synthesized and evaluated as potential sodium channel blockers in a functional, membrane potential-based assay. One member of this series displayed subnanomolar, state-dependent sodium channel block, and was orally efficacious in a mouse model of epilepsy.
Subject(s)
Anticonvulsants/pharmacology , Benzodiazepinones/pharmacology , Epilepsy/drug therapy , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Sodium Channel Blockers/pharmacology , Animals , Anticonvulsants/chemical synthesis , Anticonvulsants/pharmacokinetics , Benzodiazepinones/chemical synthesis , Benzodiazepinones/pharmacokinetics , Electrophysiology , Electroshock , Epilepsy/metabolism , Ether-A-Go-Go Potassium Channels/metabolism , Fluorescence Resonance Energy Transfer , Humans , Mice , Molecular Structure , Rats , Sodium Channel Blockers/chemical synthesis , Sodium Channel Blockers/pharmacokineticsABSTRACT
The melanocortin subtype-4 receptor (MC4R) has been implicated in the control of feeding behavior and body weight regulation. A series of tetrapeptides, based on Tic-DPhe-Arg-Trp-NH2-a mimic of the putative message sequence "His-Phe-Arg-Trp" and modified at the DPhe position, were prepared and pharmacologically characterized for potency and selectivity. Substitution of His with Tic gave peptides with significant increases in selectivity. The effects of the substitution pattern of DPhe were investigated and it has significant influences on potency and the level of the maximum cAMP accumulation. Intracerebroventricular administration of peptide 10 induced significant inhibition of cumulative overnight food intake and feeding duration in rats.
Subject(s)
Appetite Depressants/administration & dosage , Appetite Depressants/chemical synthesis , Eating/drug effects , Oligopeptides/administration & dosage , Oligopeptides/chemical synthesis , Receptor, Melanocortin, Type 4/metabolism , Animals , Appetite Depressants/metabolism , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Eating/physiology , Humans , Male , Models, Molecular , Oligopeptides/metabolism , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
Syntheses and nitric oxide synthase inhibitory activity of cyclic amidines containing 5,6- 6,6- and 7,6-fused systems are described. X-ray structure determination facilitated the assignment of the stereochemistry of the most active compounds perhydro-2-iminoisoquinoline (8a) and perhydro-2-iminopyrindine (10a). Both 8a and 10a are very potent inhibitors of iNOS, with excellent selectivity over eNOS and they are orally active in rats with long duration suitable for once or twice a day dosing.
