morphine-sulfate and Pain

Clinical human genetic studies have recently identified the tetrodotoxin (TTX) sensitive neuronal voltage gated sodium channel Nav1.7 (SCN9A) as a critical mediator of pain sensitization. Herein, we report structure-activity relationships for a novel series of 2,4-diaminotriazines that inhibit hNav1.7. Optimization efforts culminated in compound 52, which demonstrated pharmacokinetic properties appropriate for in vivo testing in rats. The binding site of compound 52 on Nav1.7 was determined to be distinct from that of local anesthetics. Compound 52 inhibited tetrodotoxin-sensitive sodium channels recorded from rat sensory neurons and exhibited modest selectivity against the hERG potassium channel and against cloned and native tetrodotoxin-resistant sodium channels. Upon oral administration to rats, compound 52 produced dose- and exposure-dependent efficacy in the formalin model of pain.

Topics: Acetamides; Administration, Oral; Analgesics; Animals; Binding Sites; Cell Line; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Formaldehyde; Ganglia, Spinal; Humans; In Vitro Techniques; Microsomes, Liver; NAV1.1 Voltage-Gated Sodium Channel; Nerve Tissue Proteins; Neurons; Pain; Pain Measurement; Patch-Clamp Techniques; Rats; Sodium Channel Blockers; Sodium Channels; Solubility; Structure-Activity Relationship; Tetrodotoxin; Triazines

A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.

Topics: Analgesia; Analgesics; Animals; Biological Assay; Bridged Bicyclo Compounds; Bridged-Ring Compounds; Gait; Indicators and Reagents; Morphine; Naloxone; Pain; Rats; Receptors, Opioid; Structure-Activity Relationship