ABSTRACT
Evidence has emerged suggesting a role for the cannabinoid CB2 receptor in immune cell motility. This provides a rationale for a novel and generalized immunoregulatory role for cannabinoid CB2 receptor-specific compounds. In support of this possibility, we will review the biology of a class of cannabinoid CB2 receptor-specific inverse agonist, the triaryl bis-sulfones. We will show that one candidate, Sch.414319, is potent and selective for the cannabinoid CB2 receptor, based on profiling studies using biochemical assays for 45 enzymes and 80 G-protein coupled receptors and ion channels. We will describe initial mechanistic studies using this optimized triaryl bis-sulfone, showing that the compound exerts a broad effect on cellular protein phosphorylations in human monocytes. This profile includes the down regulation of a required phosphorylation of the monocyte-specific actin bundling protein L-plastin. We suggest that this observation may provide a mechanism for the observed activity of Sch.414319 in vivo. Our continued analysis of the in vivo efficacy of this compound in diverse disease models shows that Sch.414319 is a potent modulator of immune cell mobility in vivo, can modulate bone damage in antigen-induced mono-articular arthritis in the rat, and is uniquely potent at blocking experimental autoimmune encephalomyelitis in the rat.
Subject(s)
Receptor, Cannabinoid, CB2/agonists , Amino Acid Sequence , Animals , Autoimmune Diseases/drug therapy , Autoimmune Diseases/physiopathology , Cell Movement/drug effects , Cell Movement/physiology , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/physiology , Molecular Sequence Data , Receptor, Cannabinoid, CB2/genetics , Sulfones/chemistry , Sulfones/pharmacologyABSTRACT
The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.
Subject(s)
Acetylcholine/metabolism , Cognition/drug effects , Muscarinic Antagonists/pharmacology , Piperazines/pharmacology , Receptors, Muscarinic/drug effects , Animals , Blood Pressure/drug effects , Brain/drug effects , Brain/metabolism , CHO Cells , Cricetinae , Heart Rate/drug effects , Male , Mice , Microdialysis , Molecular Structure , Piperazines/chemistry , Rats , Rats, Sprague-Dawley , Receptor, Muscarinic M2 , Saimiri , Scopolamine/pharmacology , Time FactorsABSTRACT
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
Subject(s)
Benzylidene Compounds/chemistry , Dioxoles/chemistry , Dioxoles/pharmacology , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Acetylcholine/analysis , Acetylcholine/metabolism , Administration, Oral , Animals , Area Under Curve , Benzylidene Compounds/metabolism , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Drug Evaluation, Preclinical , Drug Stability , Humans , Macaca fascicularis , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Muscarinic Antagonists/blood , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
Structure activity studies on [4-(phenylsulfonyl)phenyl]methylpiperazine led to the discovery of 4-cyclohexyl-alpha-[4-[[4-methoxyphenyl(S)-sufinyl]phenyl]-1-pi perazineacetonitrile, 1, an M2 selective muscarinic antagonist. Affinity at the cloned human M2 receptor was 2.7 nM; the M1/M2 selectivity is 40-fold.
Subject(s)
Benzene Derivatives/chemical synthesis , Muscarinic Antagonists/chemical synthesis , Receptors, Muscarinic/drug effects , Acetylcholine/metabolism , Administration, Oral , Alkaloids/chemistry , Alkaloids/pharmacology , Animals , Benzene Derivatives/chemistry , Benzene Derivatives/pharmacology , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Dibenzazepines/chemistry , Dibenzazepines/pharmacology , Drug Design , Furans , Humans , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Naphthalenes , Piperidines , Pyridines/chemistry , Pyridines/pharmacology , Rats , Receptor, Muscarinic M2 , Receptors, Muscarinic/physiology , Recombinant Proteins/antagonists & inhibitors , Structure-Activity RelationshipABSTRACT
Radiofrequency electromagnetic fields can affect human health not only by direct interactions but indirectly through induction of charges on isolated or poorly grounded conductive (metallic) objects located in these fields. A person who touches such an object may perceive a tingling or prickling sensation or heat, or experience pain or electric shock. For sufficiently large objects, these phenomena can occur at field strengths that are relatively low and below the health protection limits based on direct interactions. We describe a method and circuitry developed to evaluate steady-state contact currents that may flow through a person touching conductive objects and give a summary of experimental tests performed. The method is simple and viable for field tests aimed at preventing pain, shock, and burn hazards in radiofrequency electromagnetic fields except those related to spark discharges. The method is applicable up to about 30 MHz.
