title: Synthesis and biological evaluation of 5-membered spiro heterocycle-benzopyran derivatives against myocardial ischemia.
abstract: The activation of ATP-sensitive potassium channels (K(ATP)), play a key role in an endogenous "self-defence" mechanism, known as ischemic preconditioning (IPC), which is fundamentally involved in the protection of the heart against the ischemia/reperfusion injury. Presently, it is widely accepted that IPC is mainly (albeit not exclusively) mediated by the activation of K(ATP) channels expressed in the mitochondrial inner membrane (mito-K(ATP)) rather than the sarcoplasmatic ones (sarc-K(ATP)). Consistently, exogenous activation of K(ATP) channels by pharmacological tools can be viewed as one of the most promising strategies for the therapy of myocardial ischemia. As part of our research program devoted to the synthesis and the evaluation of new cardioprotective agents, we extensively studied several six-membered spiro-heterocycle-benzopyran compounds endowed of a significant anti-ischemic activity. The positive results obtained, prompted us to further explore the influence on the biopharmacological effects, of the spiro-substitution at C4 benzopyran nucleus by replacing the six-membered spirocycle of the most active compounds with 5-membered-one. The preliminary evaluation of the new compounds on cultured H9c2 cardiomyoblasts exposed to anoxia/reperfusion and on Langendorff-perfused rat hearts submitted to ischemia/reperfusion cycles, showed that some of them can exert a cardioprotective effect. This anti-ischemic activity was antagonized by 5-hydroxydecanoic acid, a selective blocker of mito-K(ATP) channels, confirming the involvement of this channel in the cardioprotective activity.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. simona.rapposelli@farm.unipi.it
authors.forename: Simona
authors.initials: S
authors.lastname: Rapposelli
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Breschi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Calderone
authors.forename: Maria
authors.initials: M
authors.lastname: Digiacomo
authors.forename: Alma
authors.initials: A
authors.lastname: Martelli
authors.forename: Lara
authors.initials: L
authors.lastname: Testai
authors.forename: Michael
authors.initials: M
authors.lastname: Vanni
authors.forename: Aldo
authors.initials: A
authors.lastname: Balsamo
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use*; D002460:Cell Line; D054086:KATP Channels / Q000378:metabolism; D008297:Male; D017202:Myocardial Ischemia / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001578:Benzopyrans; D002316:Cardiotonic Agents; D054086:KATP Channels