Calcitonin gene-related peptide (CGRP) is one of the most potent endogenous vasodilators known. This peptide is increased during migraine attacks and has been implicated in the pathogenesis of migraine headache. Here we report on the ®rst small molecule selective CGRP antagonist: BIBN4096BS. In vitro, this compound is extremely potent at primate CGRP receptors exhibiting an a nity (K i ) for human CGRP receptors of 14.4+6.3 (n=4) pM. In an in vivo model, BIBN4096BS in doses between 1 and 30 mg kg 71 (i.v.) inhibited the e ects of CGRP, released by stimulation of the trigeminal ganglion, on facial blood¯ow in marmoset monkeys. It is concluded that BIBN4096BS is a potent and selective CGRP antagonist.

The synthesis of more than fifty 36-residue oligopeptide analogs of neuropeptide Y (NPY) and their affinity to human Y, and Y, receptors is described. Each amino acid of the natural sequence was replaced by L-alanine, the four alanine residues at position 12, 14, 18 and 23 were replaced by glycine. Additional residues .were exchanged to closely related ones in order to characterize the prerequisites for binding. A combination of automated single and multiple peptide synthesis using fluoren-9-ylmethoxycarbonyl/tert-butoxy strategy was applied. The purified peptides were characterized by electrospray mass spectrometry, analytical HPLC and amino acid analysis. Binding was investigated by displacement of '251-labelled neuropeptide Y from human neuroblastoma cell lines Whereas Pro2 and the integrity of the neuropeptide Y loop is important for the binding to the Y, receptor, exchanges within the C-terminal helix affect the affinity to the Y, receptor. The Cterminal pentapeptide amide is important for both receptors and probably represents the binding site. However, Arg33 and Arg35 may not be exchanged by L-alanine in the Y, system, whereas Arg35 and Tyr36 are the most susceptible residues in the Y, system. In order to distinguish between conformational effects and direct hormone/receptor interaction via the side chains of neuropeptide Y, circular dichroic studies of the alanine-containing peptides were performed and structure affinity relationships are discussed.Comparing the affinities of the neuropeptide Y analogs to Y, and Y, receptors significant differences were found for the two binding sites, which suggests a different active conformation of neuropeptide Y at the two subtypes of receptors. Using molecular dynamics calculations, two distinct conformations were identified which are in good agreement with the data obtained by structure/ affinity investigations. SK-N-MC and SMS-KAN.Neuropeptide Y (NPY) is a 36-amino-acid amide which exhibits a high similarity to the pancreatic polypeptide and peptide YY. It was isolated from pig brain and sequenced (Tatemoto) in 1982.Information about the secondary structure of pancreatic polypetptide hormones has been obtained through the work of Blundell and co-workers who performed X-ray analyses on avian (turkey) pancreatic polypeptide Wood, 1982., Glover et al., 1983). Residues 1-8 of the crystalline avian pancreatic polypeptide form a type I1 proline helix followed by a loop (residues 9-14) and an a-helical segment (residues 15-32). The four C-terminal amino acids adopt a relatively flexible loop-like conformation. Hydrophobic interactions of the proline helix and the amphiphilic ahelix lead to the hairpin structure. Comparative circular dichroic measurements of different pancreatic polypeptides and Correspondence to A. G.

No abstract

1 The novel Y1-selective argininamide derivative BIBO 3304 ((R)-N- [[4-(aminocarbonylaminomethyl)phenyl]methyl]-N 2 -(diphenylacetyl)-argininamide tri¯uoroacetate) has been synthesized and was examined for its subtype selectivity, its in vitro antagonistic properties and its food intake inhibitory properties. 2 BIBO 3304 displayed subnanomolar anity for both the human and the rat Y1 receptor (IC 50 values 0.38+0.06 nM and 0.72+0.42 nM, respectively). The inactive enantiomer of BIBO 3304 (BIBO 3457) had low anity for both the human and rat Y1 receptor subtype (IC 50 41000 nM). BIBO 3304 showed low anity for the human Y2 receptor, human and rat Y4 receptor as well as for the human and rat Y5 receptor (IC 50 values 41000 nM). 3 30 mg BIBO 3304 administered into the paraventricular nucleus inhibited the feeding response induced by 1 mg NPY as well as the hyperphagia induced by a 24 h fast implying a role for Y1 receptors in NPY mediated feeding. The inactive enantiomer had no eect. 4 BIBO 3304 inhibits neither the galanin nor the noradrenaline induced orexigenic response, but it blocked feeding behaviour elicited by both [Leu 31 , Pro 34 ]NPY and NPY (3 ± 36) suggesting an interplay between dierent NPY receptor subtypes in feeding behavior. 5 The present study reveals that BIBO 3304 is a subtype selective nonpeptide antagonist with subnanomolar anity for the Y1 receptor subtype that signi®cantly inhibits food intake induced by application of NPY or by fasting.

No abstract

No abstract

No abstract

No abstract