A New Class of Pseudopeptide Antagonists of the Kinin B₁ Receptor Containing Alkyl Spacers

Abstract

Four previously reported kinin receptor peptide antagonists, including the B1 receptor-selective peptides desArg10-HOE 140 (H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-OH) and B-9858 (H-Lys-Lys-Arg-Pro-Hyp-Gly-Igl-Ser-D-Igl-Oic-OH), have been modified by replacement of the central tetrapeptide Pro-Hyp-Gly-Xaa with linear alkyl spacers of variable length. The analogue of desArg10-HOE 140 containing the 11-aminoundecanoic acid as spacer, MEN 11575 [H-D-Arg-Arg-NH-(CH2)10-CO-Ser-D-Tic-Oic-OH], was found to be slightly more potent than the unmodified peptide (pA2 = 7.1) as a kinin B1 receptor antagonist in the rat ileum longitudinal smooth muscle assay. Moreover, MEN 11575 is devoid of residual agonist activity at the kinin B1 receptor (rat ileum) and antagonist activity at the kinin B2 receptor (guinea pig ileum longitudinal smooth muscle). Both these activities are displayed by the parent peptide desArg10-HOE 140. Therefore, despite its greatly simplified chemical structure, MEN 11575 shows an improved pharmacological profile in terms of both potency and selectivity, and it represents a good template for the development of new peptidomimetic kinin B1 receptor antagonists. We also report an attempt to investigate the conformational role of the flexible, linear spacer of MEN 11575 and to design more constrained analogues, possibly locked in the bioactive conformation, using semirigid spacers based on Calpha-tetrasubstituted alpha-amino acids of the family of 1-aminocycloalkane-1-carboxylic acids (Acnc).

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…In the anesthetized dog representing a hemodynamic system with mixed B 1 and B 2 receptor responses (see below), B9858 is reported to be 20 times more potent than Lys- [Leu 8 ]des-Arg 9 -BK in antagonizing des-Arg 9 -BK-induced hypotension, and the antagonist effect lasts for more than 4 h (versus about 15 min for Lys- [Leu 8 ]desArg 9 -BK; Stewart et al, 1996). Numerous structural experiments have been conducted with peptide kinin antagonists, such as producing pseudopeptides that retain limited structural elements of the parent peptide (Chakravarty et al, 1995;Galoppini et al, 1999;Bedos et al, 2000), or the production of dimers of antagonists. An early implementation of the latter idea was deltibant (CP-0127), the homodimer of D ]BK coupled through the side chains of Cys 6 by the linker bis-succinimidohexane.…”

Endotoxin sensitization to kinin B1 receptor agonist in a non‐human primate model: haemodynamic and pro‐inflammatory effects

“…Moreover, several studies showed B 1 receptor activation of the cyclo‐oxygenase pathway in vascular cells or fibroblasts ( Lerner & Modeer, 1991 ; Marceau et al ., 1998 ). New, potent, peptide and non‐peptide antagonists of B 1 receptors are being developed, with inflammation‐associated hyperalgesia as a primary target condition ( Altamura et al ., 1999 ; Galoppini et al ., 1999 ; Gobeil et al ., 1999 ; Horlick et al ., 1999 ). The observation that dKD mediates oedema in green monkeys supports the assumption that B 1 receptor antagonists may be effective anti‐inflammatory tools in humans.…”

Sonication‐Induced Formation of Size‐Controlled Self‐Assemblies of Amphiphilic Janus‐Type Polymers as Optical Tumor‐Imaging Agents

“…To a solution of a part of the deprotected polymer (60 mg) in DMF (3.0 mL) were added 8‐(9 H ‐fluoren‐9‐yl)methoxycarbonylamino)octanoic acid (7.6 mg, 0.020 mmol), EDC·HCl (7.7 mg, 0.040 mmol), and HOBt (5.4 mg, 0.040 mmol) at room temperature. After stirring the reaction mixture overnight, the resulting mixture was dialyzed by using Spectra/Por 6 (MWCO: 3500) against water (Milli‐Q) for one day.…”