A new series of photoactivatable and iodinatable linear vasopressin antagonists.
A series of new linear photoactivatable and iodinatable antagonists of the neuropeptidic hormone vasopressin was designed and synthesized by a combination of PyBOP-mediated Boc/solid-phase peptide synthesis and solution synthesis approaches. These were based on modifications of a previously reported potent and selective antagonist of the vasopressor response (V1a receptor) to [arginine]vasopressin, phenylacetyl-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2. (Azidophenyl)alkyl substitutions, of the general structure N3-C6H4(CH2)nCO (n = 0, 1, 2, or 3), were employed in position 1. The seven new analogues are 4-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (3), 3-N3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (12), 4-N3-C6H4CH2-CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (13), 3-N3-C6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (14), 4-N3-C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (15), 3-N3-C6H4(CH2)2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (16), 4-N3-C6H4-(CH2)3CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (17). All analogues were tested for their affinity of the rat hepatic V1a receptor. Analogues 3 and 12 have a low affinity (Ki approximately 20 nM) and analogues 13-17 show a high affinity (Ki between 0.04 and 0.3 nM). The affinity values appear to be mainly a function of the alkyl chain length and to a lesser extent of the meta or para position of the azido group on the aromatic ring. Analogues 13-17 were iodinated on the Tyr-9 residue, giving compounds 18-22. All these five iodinated derivatives exhibited Ki values of 0.2-1 nM for rat liver membranes. Their affinities for oxytocin and renal V2 vasopressin receptors were much lower. Moreover, all analogues completely antagonized the vasopressin-stimulated inositol phosphates production in WRK1 cells and were devoided of any agonistic potency. Preliminary covalent binding studies showed improved covalent yields as compared to any previously reported results. They are very promising candidates as potential high-affinity, highly selective, photosensitive ligands for the V1a receptor. They could serve as a useful pharmacological tools for studies on the vasopressin binding site.
Carnazzi
E
E
UPR 9023 CNRS, Mécanismes Moléculaires des Communications Cellulaires, Montpellier, France.
Aumelas
A
A
Barberis
C
C
Guillon
G
G
Seyer
R
R
D000595:Amino Acid Sequence; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D005260:Female; D007202:Indicators and Reagents; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010777:Photochemistry; D051381:Rats; D017208:Rats, Wistar; D017483:Receptors, Vasopressin / Q000378:metabolism / Q000528:radiation effects; D014407:Tumor Cells, Cultured; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry; D014667:Vasopressins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
D065092:Antidiuretic Hormone Receptor Antagonists; D007202:Indicators and Reagents; D009842:Oligopeptides; D017483:Receptors, Vasopressin; D014667:Vasopressins; C068793:phenylacetyl-O-methyltyrosyl-phenylalanyl-glutaminyl-asparaginyl-prolyl-arginyl-tyrosinamide; C012385:1,3,4,6-tetrachloro-3 alpha,6 alpha-diphenylglycoluril; D014508:Urea