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

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.

Isoform Selectivity of Adenylyl Cyclase Inhibitors: Characterization of Known and Novel Compounds

“…To gain further insight into the selectivity of different AC inhibitors, we also examined NB001, which is reported to be an AC1-selective ligand with therapeutic potential as an analgesic (Zhou, 2012). In HEK cells stably expressing AC1, NB001 inhibited AC activity when stimulated with forskolin and the calcium ionophore calimycin (Wang et al, 2011). We also observed NB001 inhibition of cAMP accumulation in HEK cells transiently expressing AC1 when stimulated with ionomycin and forskolin (Fig.…”

“…4B). However, this experiment, performed both in the present study and by Wang et al (2011), detects cAMP accumulation within the cell and does not necessarily solely reflect AC1 activity. We were unable to inhibit AC1 activity in vitro by NB001 when assayed in membranes prepared from HEK293 cells expressing AC1, as used in the cAMP accumulation assays (Fig.…”

“…However, direct interaction with AC does not preclude clinical usefulness. Although the molecular mechanism for NB001 is unclear, it still has important analgesic effects in animals (Wang et al, 2011). AC1 has roles in both pain sensation (Vadakkan et al, 2006;Wang et al, 2007) and memory (Villacres et al, 1998).…”

Plasticity of Metabotropic Glutamate Receptor-Dependent Long-Term Depression in the Anterior Cingulate Cortex after Amputation

“…Animal studies of the ACC not only confirm the importance of ACC in nociception (Vogt, 2005;Zhuo, 2008Zhuo, , 2011, but also reveal molecular mechanisms for chronic pain (Zhuo, 2006(Zhuo, , 2008. While peripheral injury triggers activity-dependent immediate early genes (Zhuo, 2006(Zhuo, , 2011 and induces long-term potentiation (LTP) of excitatory synaptic responses in the ACC neurons (Wei and Zhuo, 2001;Xu et al, 2008), inhibition or genetic deletion of key molecules required for triggering LTP produces analgesic effects in animal models of chronic pain (Wei et al, 2002;Wu et al, 2005b;Wang et al, 2011). Recently, protein kinase M (PKM) has been identified as a key enzyme required to maintain such injury-related LTP (Li et al, 2010).…”

The Analgesic Effects of (5R,6R)6-(3-Propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] Octane on a Mouse Model of Neuropathic Pain: Erratum

“…(Anesth Analg 2017;124: involved in the maintenance of neuropathic pain. 12,13 Therefore, the M2 and M4 receptors may contribute to the development and maintenance of chronic pain. 9 Vedaclidine and (5R,6R)6-(3-propylthio-1,2,5-thiadiazol-4-yl)-1-azabicyclo[3.2.1] octane (PTAC) are partial muscarinic receptors ligands that have agonist effects at muscarinic M2 and M4 receptors and antagonist effects at muscarinic M1, M3, and M5 receptors.…”