Design and Synthesis of New Linear and Cyclic Bradykinin Antagonists

Abstract

We report here on the synthesis and pharmacological properties of a new series of small linear and cyclic peptides derived from the five C-terminal amino acid residues of second-generation bradykinin receptor antagonists. Variations of the two first residues of the pentapeptide (Thi-Ser-D-Tic-Oic-Arg) were shown to modulate the biological activities of the analogs on bradykinin-induced smooth muscle contractions in rabbit jugular vein (RJV), a tissue preparation specific of the B2 bradykinin receptor. Several analogs showed pA2 values around 7 on this tissue preparation, and one cyclic compound, c[-Gly-Thi-D-Tic-Oic-Arg-], 24, in which Thi-Ser was replaced by Gly-Thi, displayed a pA2 of 7.4 on RJV. On the basis of these results, three cyclic molecules and their linear counterparts (compounds 22-24 and 4-6, respectively) were tested on human umbilical vein, a tissue specific of the human B2 receptor. The pKB values obtained for these compounds on these tissue preparations were equivalent to those obtained for the decapeptide NPC 567 (4.8 < pA2 < 5.1). NMR and molecular modeling studies performed on compound 24 clearly demonstrated a type II' beta-turn structure. This analog may serve as a new lead for the design of nonpeptide ligands of the bradykinin B2 receptor subtype.

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

“…This peptidomimetic exhibits a binding affinity for the BK B2 receptor in the micromolar range, result that is consistent with the low affinity exhibited by a series of cyclic peptides designed to mimic the C-terminus of BK [13,14]. These results indicate that mimicking the C-terminus of the peptide is necessary condition to get good binding affinity, but not sufficient.…”

Crystallographically observed folded topology of an unsubstituted γ‐aminobutyric acid incorporated in a model peptide: Importance of a CH···O interaction

“…3,9 Besides, the ability of c-Abu moiety to enhance metabolic stability, coupled with unusual folding behavior of methylene units, may lead to useful medicinal properties since, dramatically altered conformational features may possibly influence and/or modulate the receptor selectivity and/ or pharmacological properties. [31][32][33][34][35][36] In conclusion, to validate the existing hypothesis, 16 we demonstrated via X-ray diffraction analysis, the existence of an unusual tightly folded topology in a designed peptide: Boc-Pro-c-Abu-OH, stabilized by N i Á Á Á HÀ ÀN i11 and C i À ÀH Á Á Á O i intramolecular hydrogen bonds. This study unambiguously established that despite the absence of an amide-functionality, the CONHÀ À(CH 2 ) 3 À ÀCOOH component of the c-Abu moiety accommodated folded orientation, stabilized by an unconventional C c À ÀH Á Á Á O interaction.…”

New insights into the stereochemical requirements of the bradykinin B1 receptor antagonists binding

“…This conclusion came from the analysis of the binding affinity of diverse cyclic peptides inspired on the C-terminus of icatibant. Thus for example compounds like the cyclo-(Gly-Thi-D-Tic-Oic-Arg) [13] or cyclo-(Pro-Orn-D-Tic-Oic-Arg) [14] show poor antagonistic affinity for the B2 receptor. Accordingly, the affinity of icatibant and analogs was rationalized in terms of the interactions of the compound with the receptor, such that the β-turn at the C-terminus was thought to occupy a hydrophobic region on the orthosteric pocket, whereas the N-terminal arginine were thought to interact with the negatively charged residues Asp 266 and Asp 284 , putatively located at the mouth of the receptor [15].…”