title: Novel approach to the design of synthetic radioiodinated linear V1A receptor antagonists of vasopressin.
abstract: We report the solid phase synthesis of six analogs of the potent and selective linear AVP vasopressor (V1a receptor) antagonist: Phaa1-D-Tyr(Et)2-Phe3-Gln4-Asn5-Lys6-Pro7-Arg-NH(8)2(A) (where Phaa = phenylacetyl) in which the Phaa1 residue is replaced by hydroxyphenylacetyl (HO-Phaa), hydroxyphenylpropionyl (HO-Phpa) and phenylpropionyl (Phpa) and the D-Tyr(Et)2 and Lys6 residues by D-Tyr(Me)2 and Arg6 substituents. The phenolic-containing peptides were synthesized to test the feasibility of using this approach for the design of high affinity selective ligands for AVP V1a receptors. The following analogs of A were synthesized: 11 [(HO)Phaa1]; 2. [(HO)Phaa1,D-Tyr(Me)2]; 3. [(HO)Phaa1,D-Tyr(Me)2, Arg6]; 4. [(HO)Phaa1,Arg6]; 5. [Phpa1]; 6. [(HO)Phpa1]. All six peptides were examined for agonistic and antagonistic potencies in vasopressor (V1a-receptor) and antidiuretic (V2-receptor) and in vitro oxytocic assays in rats. The affinities of the phenolic-containing peptides for hepatic V1a and uterine receptors were also determined. The phenolic-containing peptides all exhibit potent V1a antagonism. Their anti-V1a pA2 values range from 8.23 to 8.63 (the anti-V1a pA2 value of A = 8.69). Their inhibition constants (Ki in nM) range 0.4 to 1.0. They are weak antidiuretic agonists with activities ranging from 0.022 U/mg to 0.13 U/mg (A = 0.033 U/mg). They all exhibit OT antagonism in vitro. Their anti-OT pA2 values range from 7.28 to 7.71 (A = 7.62). All five phenolic compounds were iodinated using iodine chloride and tested in the same in vivo and in vitro assay system.(ABSTRACT TRUNCATED AT 250 WORDS)
authors: Department of Biochemistry and Molecular Biology, Medical College of Ohio, Toledo.
authors: M
authors: M
authors: Manning
authors: K
authors: K
authors: Bankowski
authors: C
authors: C
authors: Barberis
authors: S
authors: S
authors: Jard
authors: J
authors: J
authors: Elands
authors: W Y
authors: WY
authors: Chan
mesh_terms: D000595:Amino Acid Sequence; D057911:Angiotensin Receptor Antagonists; D001127:Arginine Vasopressin; D001681:Biological Assay; D015195:Drug Design; D007457:Iodine Radioisotopes; D008969:Molecular Sequence Data; D010121:Oxytocin / Q000037:antagonists & inhibitors; D019800:Phenol; D010636:Phenols / Q000737:chemistry; D010648:Phenylacetates / Q000737:chemistry; D010666:Phenylpropionates / Q000737:chemistry; D011485:Protein Binding; D017483:Receptors, Vasopressin
chemical_list: D057911:Angiotensin Receptor Antagonists; D007457:Iodine Radioisotopes; D010636:Phenols; D010648:Phenylacetates; D010666:Phenylpropionates; D017483:Receptors, Vasopressin; D001127:Arginine Vasopressin; D019800:Phenol; D010121:Oxytocin; C025136:phenylacetic acid