Binding experiments have shown that Angiotensin Converting Enzyme inhibitors (ACE-Ins) have high chemical affinity for binding sites of human somatic ACE (hsACE). The enzyme has 2 natural substrates and catalytic domains: one cleaving angiotensin-I (Ang-I) and the other inactivating bradykinin 1-9 (Bk). AIM: To test binding selectivity of various ACE-Ins - namely Enalaprilat (E), Perindoprilat (P), Quinaprilat (Q), Ramiprilat (R), Trandolaprilat (T) – for specific Ang-I and Bk binding sites of hsACE. Single displacement binding assays showed the following IC50 for ACE-Ins and hsACE natural substrates: Q: 0.35 nM, T: 0.57 nM, R: 0.76 nM, P: 1.05 nM, E:1.94 nM, Ang-I: 2.65 microM and Bk: 1.31 microM. The order of binding affinity of ACE-Ins to hsACE is: Q>T>R>P>E; (2) All ACE-Ins have a higher affinity for Bk respect to Ang-I binding sites, the order of binding affinity being E>Q>T>R>P for Ang-I and Q>E>T>R>P for Bk binding sites, respectively; (3) P is the ACE-In with the highest selectivity for Bk versus Ang-I binding sites, (the order of Bk/Ang-I selectivity being P>R>Q>T>E). These results support the hypothesis that affinity differences of ACE-Ins towards sites for Bk degradation exist and may constitute the biochemical grounds in explaining differences obtained in secondary prevention of coronary artery disease.
The ACE-inhibitor Perindoprilat has high selectivity for bradykinin binding sites of human somatic ACE
FERRARI, Roberto;CECONI, Claudio
2006
Abstract
Binding experiments have shown that Angiotensin Converting Enzyme inhibitors (ACE-Ins) have high chemical affinity for binding sites of human somatic ACE (hsACE). The enzyme has 2 natural substrates and catalytic domains: one cleaving angiotensin-I (Ang-I) and the other inactivating bradykinin 1-9 (Bk). AIM: To test binding selectivity of various ACE-Ins - namely Enalaprilat (E), Perindoprilat (P), Quinaprilat (Q), Ramiprilat (R), Trandolaprilat (T) – for specific Ang-I and Bk binding sites of hsACE. Single displacement binding assays showed the following IC50 for ACE-Ins and hsACE natural substrates: Q: 0.35 nM, T: 0.57 nM, R: 0.76 nM, P: 1.05 nM, E:1.94 nM, Ang-I: 2.65 microM and Bk: 1.31 microM. The order of binding affinity of ACE-Ins to hsACE is: Q>T>R>P>E; (2) All ACE-Ins have a higher affinity for Bk respect to Ang-I binding sites, the order of binding affinity being E>Q>T>R>P for Ang-I and Q>E>T>R>P for Bk binding sites, respectively; (3) P is the ACE-In with the highest selectivity for Bk versus Ang-I binding sites, (the order of Bk/Ang-I selectivity being P>R>Q>T>E). These results support the hypothesis that affinity differences of ACE-Ins towards sites for Bk degradation exist and may constitute the biochemical grounds in explaining differences obtained in secondary prevention of coronary artery disease.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
