ABSTRACT
Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms.
Subject(s)
Cryopyrin-Associated Periodic Syndromes/prevention & control , Nicotinic Acids/therapeutic use , Peripheral Nerve Injuries/complications , TRPM Cation Channels/antagonists & inhibitors , Animals , Behavior, Animal/drug effects , Calcium/metabolism , Cryopyrin-Associated Periodic Syndromes/etiology , Cryopyrin-Associated Periodic Syndromes/metabolism , Disease Models, Animal , Electrophysiological Phenomena , HEK293 Cells , Humans , Male , Nicotinic Acids/administration & dosage , Nicotinic Acids/pharmacology , Peripheral Nerve Injuries/metabolism , Peripheral Nerve Injuries/psychology , Rats , Rats, Sprague-DawleyABSTRACT
Development of a lead series of piperidinylurea CXCR3 antagonists has led to the identification of molecules with alternative linkages which retain good potency. A novel 5-(piperidin-4-yl)amino-1,2,4-thiadiazole derivative was found to have satisfactory in vitro metabolic stability and to be orally bioavailable in mice, giving high plasma concentrations and a half life of 5.4h.
Subject(s)
Azoles/chemical synthesis , Azoles/pharmacology , Piperidines/chemistry , Receptors, CXCR3/antagonists & inhibitors , Amination , Animals , Azoles/chemistry , CHO Cells , Cricetinae , Cricetulus , Humans , Mice , Models, Molecular , Molecular Structure , Receptors, CXCR3/metabolism , Structure-Activity Relationship , Water/chemistryABSTRACT
The study of non-oxazole containing indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis and in vitro inhibitory values for IMPDH II are discussed.
Subject(s)
Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/pharmacology , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Hydrogen Bonding , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Molecular Weight , Oxazoles/pharmacology , Phenylurea Compounds/chemistry , Phenylurea Compounds/pharmacology , Sensitivity and Specificity , Structure-Activity RelationshipABSTRACT
The elaboration of previously reported indole fragments as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II, PBMC proliferation and physicochemical properties are discussed.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Indoles/chemical synthesis , Indoles/pharmacology , Biological Transport, Active/drug effects , Caco-2 Cells , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Enzyme Inhibitors/chemistry , Humans , In Vitro Techniques , Indoles/chemistry , Leukocytes, Mononuclear/drug effects , Molecular Structure , Molecular Weight , Structure-Activity RelationshipABSTRACT
The synthesis and biological activity of a novel series of 7-methoxy-6-oxazol-5-yl-2,3-dihydro-1H-quinazolin-4-ones are described. Some of these compounds were found to be potent inhibitors of inosine 5'-monophosphate dehydrogenase type II (IMPDH II).
Subject(s)
Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemistry , Quinazolines/pharmacology , Enzyme Inhibitors/chemical synthesis , Humans , Molecular Conformation , Quinazolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
The development of a series of novel quinazolinethiones and quinazolinediones as inhibitors of inosine monophosphate dehydrogenase (IMPDH) is described. The synthesis, in vitro inhibitory values for IMPDH II and in vitro inhibitory value for PBMC proliferation are discussed.
Subject(s)
IMP Dehydrogenase/antagonists & inhibitors , Quinazolines/chemical synthesis , Quinazolines/pharmacology , Blood Cells , Cell Proliferation/drug effects , Enzyme Inhibitors/chemical synthesis , Humans , Inhibitory Concentration 50 , Ketones/chemical synthesis , Ketones/pharmacology , Monocytes/drug effects , Structure-Activity Relationship , Thiones/chemical synthesis , Thiones/pharmacologyABSTRACT
The syntheses and pharmacological profiles of some 2-trifluoromethyl-8-methoxyquinoline-5-carboxamides are described. SCH351591 is a potent selective inhibitor of phosphodiesterase type 4 (PDE4).
