Wednesday, May 8, 2024
5/8/2024
Chronic pain costs the US more than $635 billion per year, however, patients fail to receive adequate relief from the available drugs and often become drug-dependent. These observations highlight the importance for identifying new agents acting on unique targets to treat chronic pain. Genetic, neurobiological, and preclinical studies have suggested that adenylyl cyclase type 1 (AC1) may provide that new drug target. AC1 knock out mice (AC1-/-) show reduced or absent inflammatory and neuropathic pain when compared to littermate controls. Preclinical studies with a small molecule inhibitor of AC1, NB001 revealed that NB001 reduced chronic pain responses (i.e. inflammatory and neuropathic) in both mice and rats. Similarly, we have recently shown that a novel AC1 inhibitor, ST034307 also reduced inflammatory pain in a mouse model. These studies are consistent with the premise that AC1 is a new target for inhibitors of chronic pain. Unfortunately, both NB001 and ST034307 have significant issues and liabilities preventing further development. To that end, we have recently screened a chemical library collection that allowed us to identify a pyrimidinone scaffold for the development of novel AC1 inhibitors. This scaffold was prioritized for hit-to-lead optimization based on several promising criteria. Preliminary structure-activity relationship (SAR) studies have revealed for the first time compounds with sub-micromolar potency at AC1, as well as selectivity versus the closely-related AC8. Further, initial in vivo studies with a more soluble pyrimidinone benzlamine analog revealed analgesic activity in an animal model of chronic pain. Despite these promising observations, the inhibitory mechanism is unknown. The effect of chronic treatment with our lead compounds on cAMP signaling and opioid receptor modulation of AC1 are also unknown. We propose a molecular pharmacology characterization of our lead inhibitors of AC1 activity under the following Goals: Goal 1 will use site-directed mutagenesis to examine how the regulatory properties (e.g. Ca2+/CaM, Gas, and forskolin) influence to the activity of the inhibitors. Goal 2 will establish the pharmacological activity using an in vitro model to explore the effects of AC1 inhibition on m opioid receptor regulation of cAMP accumulation under both acute and chronic conditions. The studies will significanlty and rationally expand Aim 2 of the parent R01 providing insight regarding the potential Ca2+/CaM-dependent and -independent mechanisms for AC1 inhibition. Further, the studies in Goal 2 will be instrumental in understanding the translational components of the original Aim 3 by assessing efficacy, tolerance, and dependence using in vitro models.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
