A selective adenylyl cyclase 1 inhibitor relieves pain without causing tolerance

Abstract

Adenylyl cyclases (ACs) catalyze the production of the second messenger cyclic adenosine monophosphate from adenosine triphosphate. Among the ten different AC isoforms, studies with knockout animals indicate that inhibition of AC1 can relieve pain and reduce behaviors linked to opioid dependence. We previously identified ST034307 as a selective inhibitor of AC1. The development of an AC1-selective inhibitor now provides the opportunity to further study the therapeutic potential of inhibiting this protein in pre-clinical animal models of pain and related adverse reactions. In the present study we have shown that ST034307 relieves pain in mouse models of formalin-induced inflammatory pain, acid-induced visceral pain, and acid-depressed nesting. In addition, ST034307 did not cause analgesic tolerance after chronic dosing. We also show that the compound is restricted to the periphery following subcutaneous injections and report the predicted molecular interaction between ST034307 and AC1. Our results indicate that AC1 inhibitors represent a promising new class of analgesic agents that treat pain and appear to produce less adverse effects than currently-used opioids.