Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.

Discovery of Novel 1,3,8-Triazaspiro[4.5]decane Derivatives That Target the c Subunit of F1/FO-Adenosine Triphosphate (ATP) Synthase for the Treatment of Reperfusion Damage in Myocardial Infarction

Morciano, Giampaolo
Co-primo
;
Preti, Delia
Co-primo
;
PEDRIALI, GAIA
Co-primo
;
Aquila, Giorgio
Secondo
;
Missiroli, Sonia;Fantinati, Anna;CAROCCIA, NATASCIA;Pacifico, Salvatore;Bonora, Massimo;Talarico, Anna;Morganti, Claudia;Rizzo, Paola;Ferrari, Roberto;Campo, Gianluca;Giorgi, Carlotta;Trapella, Claudio
Penultimo
;
Pinton, Paolo
Ultimo
2018

Abstract

Recent cardiology research studies have reported the role, function, and structure of the mitochondrial permeability transition pore (mPTP) and have shown that its opening plays a key role in the progression of myocardial cell death secondary to reperfusion. In this manuscript, we validated a new pharmacological approach as an adjunct to reperfusion in myocardial infarction (MI) treatment and describe the discovery, optimization, and structure-activity relationship (SAR) studies of the first small-molecule mPTP opening inhibitors based on a 1,3,8-triazaspiro[4.5]decane scaffold that targets the c subunit of the F1/FO-ATP synthase complex. We identified three potential compounds with good mPTP inhibitory activity and beneficial effects in a model of MI, including a decreased apoptotic rate in the whole heart and overall improvement of cardiac function upon administration during reperfusion. The selected compounds did not show off-target effects at the cellular and mitochondrial levels. Moreover, the compounds preserved the mitochondrial ATP content despite interacting with the ATP synthase complex.
2018
Morciano, Giampaolo; Preti, Delia; Pedriali, Gaia; Aquila, Giorgio; Missiroli, Sonia; Fantinati, Anna; Caroccia, Natascia; Pacifico, Salvatore; Bonora, Massimo; Talarico, Anna; Morganti, Claudia; Rizzo, Paola; Ferrari, Roberto; Wieckowski, Mariusz R.; Campo, Gianluca; Giorgi, Carlotta; Trapella, Claudio; Pinton, Paolo
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2397146
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