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 vasopresso r response (V-1a receptor) to [arginine] vasopressin, lacetyl-D-Tyr(Me )-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2. (Azidophenyl)alkyl substitutions, o f the general structure N-3-C6H4(CH2)(n)CO (n = 0, 1, 2, or 3),were em ployed in position 1. The seven new analogues are 3-C6H4CO-D-Tyr(Me)-P he-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (3), 3-C6H4CO-D-Tyr(Me)-Phe-Gln-Asn-Arg -Pro-Arg-Tyr-NH2 (12), 6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr- NH2 (13), 6H4CH2CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (14), H2) (2)CO-D-Tyr(Me)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (15), H2)(2)CO-D-Tyr(M e)-Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH2 (16), H2)(3)CO-D-Tyr(Me)-Phe-Gln-As n-Arg-Pro-Arg-Tyr-NH2 (17). All analogues were tested for their affini ty of the rat hepatic V-1a, receptor. Analogues 3 and 12 have a low af finity (K-i approximate to 20 nM) and analogues 13-17 show a high affi nity (Ki between 0.04 and 0.3 nM). The affinity values appear to be ma inly a function of the alkyl chain length and to a lesser extent of th e meta or para position of the azido group on the aromatic ring. Analo gues 13-17 were iodinated on the Tyr-9 residue, giving compounds 18-22 . All these five iodinated derivatives exhibited K-i values of 0.2-1 n M for rat liver membranes. Their affinities for oxytocin and renal V-2 vasopressin receptors were much lower. Moreover, all analogues comple tely antagonized the vasopressin-stimulated inositol phosphates produc tion in WRK(1) cells and were devoided of any agonistic potency. Preli minary covalent binding studies showed improved covalent yields as com pared to any previously reported results. They are very promising cand idates as potential high-affinity, highly selective, photosensitive li gands for the V-1a receptor. They could serve as useful pharmacologica l tools for studies on the vasopressin binding site.