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PubMed1999

Pharmacological characterisation of the first non-peptide bradykinin B2 receptor agonist FR 190997: an in vitro study on human, rabbit and pig vascular B2 receptors.

FR 190997, a new kinin B2 receptor agonist of non-peptide nature, has been studied in three isolated vessels: the human umbilical vein (hUV), the rabbit jugular vein (rbJV), and the pig coronary artery (pCA). Bradykinin (BK) contracts the hUV and rbJV through smooth muscle B2 receptors, while it relaxes the pCA through endothelial receptors of the B2 type. Contractions of the hUV and rbJV in response to FR 190997 show slow onset and are not reproducible compared to the rapid and reproducible effect of BK. They reach only 70% and 30% of the BK-induced maximal contractions in the hUV and rbJV, respectively. The effects of FR 190997 are antagonised by HOE 140 and this antagonist shows similar pK(B) values against BK and FR 190997, indicating that the non-peptide agent interacts with the kinin B2 receptor. FR 190997 is inactive as relaxant of the pCA; in this tissue, it acts as a pure and competitive antagonist, with a pK(B) value of 7.6, while HOE 140 acts as an insurmountable antagonist (pK(B) 9.3). When tested as an antagonist, FR 190997 inhibits also the contractile effects of BK in the hUV (pK(B) 7.8) and in the rbJV (pK(B) 7.6). FR 190997 is selective for the B2 receptor since it does not interact with the B1, and is specific since it does not affect the contraction evoked by 5-hydroxytryptamine, endothelin-1, and noradrenaline in the hUV, or the relaxation induced by substance P in the pCA. FR 190997 shows therefore different pharmacological profiles in various preparations, acting as a partial agonist in the hUV and especially in the rbJV and as a pure antagonist in the pCA. This new compound could be of interest in understanding how non-peptide agonists may activate receptors for peptides.

Adrenergic beta-Antagonists↗

PubMed1998

Structure-activity study of the nociceptin(1-13)-NH2 N-terminal tetrapeptide and discovery of a nociceptin receptor antagonist.

In the present study, the minimal fragment sequence required to fully activate the nociceptin (NC) receptor, namely NC(1-13)-NH2, was used as template for the design of a series of new compounds. Changes were made in the N-terminal tetrapeptide Phe-Gly-Gly-Phe, which has been shown to be essential for receptor occupation and activation. The new compounds were tested for their ability to inhibit the electrically evoked contraction of the mouse vas deferens, a pharmacological preparation sensitive to NC. Results obtained indicate that (a) the replacement of Gly2 or Gly3 with an aromatic residue (Phe) of L or D chirality eliminates the ability of the peptide to occupy the NC receptor; (b) the distance between Phe1 and Phe4 of NC appears to be critical, since any alteration of it leads to a marked decrease or a total elimination of biological activity; and (c) the insertion of a pseudopeptide bond between Phe1 and Gly2 maintains affinity but eliminates the ability of the peptide to activate the NC receptor and leads to antagonism. The peptide [Phe1psi(CH2-NH)Gly2]-NC(1-13)-NH2 acts as a selective NC receptor antagonist and is inactive on opioid receptors. The results summarized in this paper confirm and extend our previous findings by showing that the structural requirements for NC binding to its receptor are clearly different from those of opioids; in addition, this structure-activity study has led to the identification of the first NC receptor selective antagonist.

Animals↗