title: Identification of a selective small-molecule inhibitor of type 1 adenylyl cyclase activity with analgesic properties.
abstract: Adenylyl cyclase 1 (AC1) belongs to a group of adenylyl cyclases (ACs) that are stimulated by calcium in a calmodulin-dependent manner. Studies with AC1 knockout mice suggest that inhibitors of AC1 may be useful for treating pain and opioid dependence. However, nonselective inhibition of AC isoforms could result in substantial adverse effects. We used chemical library screening to identify a selective AC1 inhibitor with a chromone core structure that may represent a new analgesic agent. After demonstrating that the compound (ST034307) inhibited Ca2+-stimulated adenosine 3',5'-monophosphate (cAMP) accumulation in human embryonic kidney (HEK) cells stably transfected with AC1 (HEK-AC1 cells), we confirmed selectivity for AC1 by testing against all isoforms of membrane-bound ACs. ST034307 also inhibited AC1 activity stimulated by forskolin- and Gαs-coupled receptors in HEK-AC1 cells and showed inhibitory activity in multiple AC1-containing membrane preparations and mouse hippocampal homogenates. ST034307 enhanced μ-opioid receptor (MOR)-mediated inhibition of AC1 in short-term inhibition assays in HEK-AC1 cells stably transfected with MOR; however, the compound blocked heterologous sensitization of AC1 caused by chronic MOR activation in these cells. ST034307 reduced pain responses in a mouse model of inflammatory pain. Our data indicate that ST034307 is a selective small-molecule inhibitor of AC1 and suggest that selective AC1 inhibitors may be useful for managing pain.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Center for Drug Discovery, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Tarsis F
authors.identifier: 0000-0003-0912-8273
authors.initials: TF
authors.lastname: Brust
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Center for Drug Discovery, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Doungkamol
authors.identifier: 0000-0003-4221-8895
authors.initials: D
authors.lastname: Alongkronrusmee
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Center for Drug Discovery, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Monica
authors.identifier: 0000-0003-4895-413X
authors.initials: M
authors.lastname: Soto-Velasquez
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Tanya A
authors.identifier: 0000-0001-7142-639X
authors.initials: TA
authors.lastname: Baldwin
authors.affiliation: Department of Chemistry and Centers for Cancer Research and Drug Discovery, College of Science, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA.
authors.forename: Zhishi
authors.identifier: 0000-0001-8379-5328
authors.initials: Z
authors.lastname: Ye
authors.affiliation: Department of Chemistry and Centers for Cancer Research and Drug Discovery, College of Science, Purdue University, 720 Clinic Drive, West Lafayette, IN 47907, USA.
authors.forename: Mingji
authors.initials: M
authors.lastname: Dai
authors.affiliation: Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Carmen W
authors.identifier: 0000-0003-1210-4280
authors.initials: CW
authors.lastname: Dessauer
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Center for Drug Discovery, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA.
authors.forename: Richard M
authors.identifier: 0000-0002-9957-1633
authors.initials: RM
authors.lastname: van Rijn
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology and Center for Drug Discovery, College of Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA. wattsv@purdue.edu.
authors.forename: Val J
authors.identifier: 0000-0003-1581-2936
authors.initials: VJ
authors.lastname: Watts
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000235:genetics / Q000378:metabolism*; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects* / Q000235:genetics; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology; D006801:Humans; D051379:Mice; D010146:Pain / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000700:Analgesics; D017450:Receptors, Opioid, mu; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; C106670:adenylyl cyclase 1