Faculty Opinions recommendation of Identification of an adenylyl cyclase inhibitor for treating neuropathic and inflammatory pain.

2011 ◽  
Author(s):  
Mellar Davis
Keyword(s):  
Adenylyl Cyclase ◽  
Inflammatory Pain ◽  
Adenylyl Cyclase Inhibitor

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

2011 ◽  
Vol 3 (65) ◽  
pp. 65ra3-65ra3 ◽  
Author(s):  
H. Wang ◽  
H. Xu ◽  
L.-J. Wu ◽  
S. S. Kim ◽  
T. Chen ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Inflammatory Pain ◽  
Adenylyl Cyclase Inhibitor

scholarly journals The Capacity to Secrete Insulin Is Dose-Dependent to Extremely High Glucose Concentrations: A Key Role for Adenylyl Cyclase

Metabolites ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 401
Author(s):  
Katherine M. Gerber ◽  
Nicholas B. Whitticar ◽  
Daniel R. Rochester ◽  
Kathryn L. Corbin ◽  
William J. Koch ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Adenylyl Cyclase ◽  
Human Islets ◽  
Adenylyl Cyclase Activity ◽  
World Record ◽  
Glucokinase Activator ◽  
Amplifying Pathway ◽  
Dose Dependent ◽  
Adenylyl Cyclase Inhibitor ◽  
Cyclase Activator

Insulin secretion is widely thought to be maximally stimulated in glucose concentrations of 16.7-to-30 mM (300-to-540 mg/dL). However, insulin secretion is seldom tested in hyperglycemia exceeding these levels despite the Guinness World Record being 147.6 mM (2656 mg/dL). We investigated how islets respond to 1-h exposure to glucose approaching this record. Insulin secretion from human islets at 12 mM glucose intervals dose-dependently increased until at least 72 mM glucose. Murine islets in 84 mM glucose secreted nearly double the insulin as in 24 mM (p < 0.001). Intracellular calcium was maximally stimulated in 24 mM glucose despite a further doubling of insulin secretion in higher glucose, implying that insulin secretion above 24 mM occurs through amplifying pathway(s). Increased osmolarity of 425-mOsm had no effect on insulin secretion (1-h exposure) or viability (48-h exposure) in murine islets. Murine islets in 24 mM glucose treated with a glucokinase activator secreted as much insulin as islets in 84 mM glucose, indicating that glycolytic capacity exists above 24 mM. Using an incretin mimetic and an adenylyl cyclase activator in 24 mM glucose enhanced insulin secretion above that observed in 84 mM glucose while adenylyl cyclase inhibitor reduced stimulatory effects. These results highlight the underestimated ability of islets to secrete insulin proportionally to extreme hyperglycemia through adenylyl cyclase activity.

Antinociceptive effects of the adenylyl cyclase inhibitor ST034307 on tooth-movement-induced nociception in rats

2019 ◽  
Vol 98 ◽  
pp. 81-86 ◽  
Author(s):  
Yangfan Cheng ◽  
Peina Huang ◽  
Bowen Meng ◽  
Lei Gan ◽  
Dongle Wu ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
Tooth Movement ◽  
Antinociceptive Effects ◽  
Adenylyl Cyclase Inhibitor

scholarly journals Optimization of a Pyrimidinone Series for Selective Inhibition of Ca2+/Calmodulin-Stimulated Adenylyl Cyclase 1 Activity for the Treatment of Chronic Pain

2021 ◽  
Author(s):  
Jason Scott ◽  
Monica Soto-Velasquez ◽  
Michael Hayes ◽  
Justin Lavigne ◽  
Heath Miller ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Physicochemical Properties ◽  
Adenylyl Cyclase ◽  
Learning And Memory ◽  
Inflammatory Pain ◽  
Selective Inhibition ◽  
Behavioral Studies ◽  
Morphine Administration ◽  
Ic50 Values ◽  
Pain Sensitization

Adenylyl cyclase type 1 is an emerging target for the treatment of chronic pain that is downstream on the analgesic pathway from the traditional µ-opioid receptor. AC1 is expressed in the central nervous system and critical for signaling in pain sensitization. Behavioral studies have revealed AC1 knockout mice exhibit reduced behavioral pain sensitization responses similar to morphine administration. AC1, and a closely related isoform AC8, are also implicated to have a role in learning and memory signaling processes. However, reports suggest selectively targeting AC1 over AC8 may be a viable strategy to eliminate potential deleterious effects on learning and memory. Our team has carried out cellular screening for inhibitors of AC1 that yielded a pyrazolyl-pyrimidinone scaffold with potency comparable to previously published AC1 inhibitors, selectivity versus AC8, and improved drug-like physicochemical properties. Structure-activity relationship (SAR) studies produced 36 analogs that balanced improvements in potency with cellular IC50 values as low as 0.25 µM and selectivity versus AC8. Prioritized analogs were selective for AC1 compared to other AC isoforms and other common neurological targets. A representative analog was assessed for efficacy in a mouse model of inflammatory pain and displayed modest anti-allodynic effects. This series of compounds represents the most potent and selective inhibitors of Ca2+/Calmodulin-stimulated AC1 activity to date with reduced off-target liabilities and improved drug-like physicochemical properties making them promising lead compounds for the treatment of inflammatory pain.

scholarly journals Analgesic effects of adenylyl cyclase inhibitor NB001 on bone cancer pain in a mouse model

2016 ◽  
Vol 12 ◽  
pp. 174480691665240 ◽  
Author(s):  
Wen-bo Kang ◽  
Qi Yang ◽  
Yan-yan Guo ◽  
Lu Wang ◽  
Dong-sheng Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Cancer Pain ◽  
Adenylyl Cyclase ◽  
Bone Cancer ◽  
Bone Cancer Pain ◽  
Analgesic Effects ◽  
Adenylyl Cyclase Inhibitor

scholarly journals Discovery of Novel Adenylyl Cyclase Inhibitor by Cell-Based Screening

2014 ◽  
Vol 37 (10) ◽  
pp. 1689-1693 ◽  
Author(s):  
Hiroki Mano ◽  
Tetsuya Ishimoto ◽  
Takuya Okada ◽  
Naoki Toyooka ◽  
Hisashi Mori
Keyword(s):  
Adenylyl Cyclase ◽  
Adenylyl Cyclase Inhibitor

scholarly journals Inhibition of calcium-stimulated adenylyl cyclase subtype 1 (AC1) for the treatment of neuropathic and inflammatory pain in adult female mice

2021 ◽  
Vol 17 ◽  
pp. 174480692110216
Author(s):  
Zhaoxiang Zhou ◽  
Wantong Shi ◽  
Kexin Fan ◽  
Man Xue ◽  
Sibo Zhou ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Animal Models ◽  
Adenylyl Cyclase ◽  
Adult Female ◽  
Inflammatory Pain ◽  
Long Term Potentiation ◽  
Anterior Cingulate ◽  
Therapeutic Drug ◽  
Female Mice ◽  
Genetic Deletion

Cortical long-term potentiation (LTP) serves as a cellular model for chronic pain. As an important subtype of adenylyl cyclases (ACs), adenylyl cyclase subtype 1 (AC1) is critical for the induction of cortical LTP in the anterior cingulate cortex (ACC). Genetic deletion of AC1 or pharmacological inhibition of AC1 blocked behavioral allodynia in animal models of neuropathic and inflammatory pain. Our previous experiments have identified a lead candidate AC1 inhibitor, NB001, which is highly selective for AC1 over other AC isoforms, and found that NB001 is effective in inhibiting behavioral allodynia in animal models of chronic neuropathic and inflammatory pain. However, previous experiments were carried out in adult male animals. Considering the potential gender difference as an important issue in researches of pain and analgesia, we investigated the effect of NB001 in female chronic pain animal models. We found that NB001, when administered orally, has an analgesic effect in female animal models of neuropathic and inflammatory pain without any observable side effect. Genetic deletion of AC1 also reduced allodynia responses in models of neuropathic pain and chronic inflammation pain in adult female mice. In brain slices of adult female mice, bath application of NB001(20 μM) blocked the induction of LTP in ACC. Our results indicate that calcium-stimulated AC1 is required for injury-related cortical LTP and behavioral allodynia in both sexes of adult animals, and NB001 can be used as a potential therapeutic drug for treating neuropathic and inflammatory pain in man and woman.

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