Introduction
MEN 11270 (H-DArg-Arg-Pro-Hyp-Gly-Thi-c(Dab-Dtic-Oic-Arg)c(7γ-10α)) is a novel selective constrained peptide antagonist, with potency and selectivity comparable to those of the linear peptide antagonist, supporting the hypothesis that a constrained C-terminal β-turn conformation preserves a high affinity for the interaction of Icatibant with the B2 kinin receptor.
Pharmacologic action
Owing to the structural similarity between MEN 11270 and icatibant, it is assumed that the mode of interaction of these two peptide antagonists with the B2 receptor may largely overlap. Although MEN 11270 possesses high affinity and selectivity for the kinin B2receptor, its affinity is slightly lower than that of Icatibant (two- to six-fold depending on experimental conditions), suggesting which indicates that the interaction mode is not completely overlapped.
Fig. 1. Chemical structure of Icatibant and MEN 11270. (Cucchi et al. 2002)
The affinity of MEN 11270 is significantly decreased by the unfavorable proximity to the Lys111 positive charge in the Ser111Lys mutant. Moreover, the decrease in affinity at the three receptors of the Ala10 derivative of MEN 11270 suggests the loss of some favourable interaction between the Arg10 side chain of MEN 11270 and the receptor. The charge interaction relevance is confirmed by the derivative [Glu10]-MEN 11270; similarly, to [Ala10]-Icatibant, the affinity of [Glu10]-MEN 11270 at the WT receptor is lower than that of MEN 11270 for the possible loss of some favorable interaction, with the additional unfavorable presence of a negative charge. The affinity towards Ser111Lys is restored to the value of MEN 11270 at the WT receptor, which means an equivalent point charge interaction.
Function
An increase in airway selectivity after i.t. administration is also observed for MEN 11270 and Icatibant. Although the profile of action of these two peptide antagonists is virtually the same after i.v. administration, the degree of blockade of BK-induced bronchoconstriction after topical delivery to the airways seems more intense/prolonged with MEN 11270 than for Icatibant.
Pharmacokinetics and metabolism
Data indicate that both drugs are substantially resistant to degradation in guinea pig plasma and liver and chemical modification of these structures (both derived from BK) has produced a substantial reduction in degradation by peptidases. Although icatibant is relatively resistant to degradation for short periods of incubation in homogenates of guinea pig lung, a substantial degradation of this compound is also observed after 4 and 24 h, whereas MEN 11270 is not degraded at all for up to 24 h of incubation. Therefore, the present data indicate the existence of an enzymatic activity in homogenates of guinea pig lung, which slowly but efficiently degrades icatibant but not MEN 11270.
References:
1. S. Meini, L. Quartara, A. Rizzi, R. Patacchini, P. Cucchi, A. Giolitti, G. Calò, D. Regoli, M. Criscuoli and C. A. Maggi. MEN 11270, a novel selective constrained peptide antagonist with high affinity at the human B2 kinin receptor. J. Pharmacol. Exp. Ther., 1999, 289(3), 1250-1256.
2. Tramontana, M., Lecci, A., Meini, S., Montserrat, X., Pascual, J., Giuliani, S., ... M. Tramontana, A. Lecci, S. Meini, X. Montserrat, J. Pascual, S. Giuliani, L. Quartara and C. A. Maggi. Differences between Peptide and Nonpeptide B2Bradykinin Receptor Antagonists in Blocking Bronchoconstriction and Hypotension Induced by Bradykinin in Anesthetized Guinea Pigs. J. Pharmacol. Exp. Ther., 2001, 296(3), 1051-1057.
3. P. Cucchi, S. Meini, L. Quartara, A. Giolitti, S. Zappitelli, L. Rotondaro and C. A. Maggi. Interaction of linear and cyclic peptide antagonists at the human B2 kinin receptor. Peptides, 2002, 23(8), 1457-1463.
