2. Academic Validation
  3. Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation

Explorations of Agonist Selectivity for the α9* nAChR with Novel Substituted Carbamoyl/Amido/Heteroaryl Dialkylpiperazinium Salts and Their Therapeutic Implications in Pain and Inflammation

  • J Med Chem. 2024 Jun 13;67(11):8642-8666. doi: 10.1021/acs.jmedchem.3c02429.
Hina Andleeb 1 2,  Roger L Papke 3,  Clare Stokes 3,  Katrin Richter 4,  Sara M Herz 5,  Ka Chiang 5,  Siva R Raju Kanumuri 6,  Abhisheak Sharma 6,  M Imad Damaj 5,  Veronika Grau 4,  Nicole A Horenstein 1,  Ganesh A Thakur 2
Affiliations

Affiliations

  • 1 Department of Chemistry, University of Florida, P.O. Box 117200, Gainesville, Florida 32611-7200, United States.
  • 2 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Bouvé College of Health Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
  • 3 Department of Pharmacology and Therapeutics, University of Florida, P.O. Box 100267, Gainesville, Florida 32610, United States.
  • 4 Department of General and Thoracic Surgery, Laboratory of Experimental Surgery, Justus-Liebig-University, German Center for Lung Research [DZL], Cardio-Pulmonary Institute [CPI], Giessen 35385, Germany.
  • 5 Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298, United States.
  • 6 Department of Pharmaceutics, University of Florida, Gainesville, Florida 32610, United States.
PMID: 38748608 DOI: 10.1021/acs.jmedchem.3c02429
Abstract

There is an urgent need for nonopioid treatments for chronic and neuropathic pain to provide effective alternatives amid the escalating opioid crisis. This study introduces novel compounds targeting the α9 nicotinic acetylcholine receptor (nAChR) subunit, which is crucial for pain regulation, inflammation, and inner ear functions. Specifically, it identifies novel substituted carbamoyl/amido/heteroaryl dialkylpiperazinium iodides as potent agonists selective for human α9 and α9α10 over α7 nAChRs, particularly compounds 3f, 3h, and 3j. Compound 3h (GAT2711) demonstrated a 230 nM potency as a full agonist at α9 nAChRs, being 340-fold selective over α7. Compound 3c was 10-fold selective for α9α10 over α9 nAChR. Compounds 2, 3f, and 3h inhibited ATP-induced interleukin-1β release in THP-1 cells. The analgesic activity of 3h was fully retained in α7 knockout mice, suggesting that analgesic effects were potentially mediated through α9* nAChRs. Our findings provide a blueprint for developing α9*-specific therapeutics for pain.

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