Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain

Sci Transl Med. 2011 Jan 12;3(65):65ra3. doi: 10.1126/scitranslmed.3001269.

Abstract

Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury-induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / analogs & derivatives*
  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / pharmacology
  • Adenosine Triphosphate / therapeutic use
  • Adenylyl Cyclase Inhibitors*
  • Adenylyl Cyclases
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Analgesics / therapeutic use*
  • Animals
  • Behavior, Animal / drug effects
  • Brain / anatomy & histology
  • Brain / physiology
  • Cell Line
  • Chronic Disease
  • Drug Discovery
  • Emotions / drug effects
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Hyperalgesia / drug therapy
  • Hyperalgesia / physiopathology
  • Inflammation / physiopathology*
  • Isoenzymes / antagonists & inhibitors
  • Long-Term Potentiation / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Molecular Structure
  • Motor Activity / drug effects
  • Neuralgia / drug therapy*
  • Neuralgia / physiopathology
  • Neurons / drug effects
  • Neurons / enzymology*
  • Neuropsychological Tests
  • Pain Measurement
  • Patch-Clamp Techniques
  • Rats
  • Receptors, Glutamate / metabolism

Substances

  • 5-((2-(6-Amino-9H-purin-9-yl) ethyl) amino)-1-pentanol
  • Adenylyl Cyclase Inhibitors
  • Analgesics
  • Enzyme Inhibitors
  • Isoenzymes
  • Receptors, Glutamate
  • Adenosine Triphosphate
  • Adenylyl Cyclases
  • adenylyl cyclase 1