title: A minor modification of residue 1 in potent vasopressin antagonists dramatically reduces agonist activity.
abstract: [1-(beta,beta-Pentamethylene-beta-mercaptopropionic acid),2-(O-ethyl)-D- tyrosine,4-valine,9-desglycine]arginine-vasopressin (SK&F 101926, 1), a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and shown to be a full antidiuretic agonist. A new animal model for vasopressin activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK&F 101926. In this model we have discovered that substitution of a cis-4'-methyl group on the Pmp moiety at residue 1 of vasopressin antagonists results in substantially reduced agonist activity compared to the unsubstituted molecule (SK&F 101926). The corresponding analogue with a trans-4'-methyl group exhibits more agonist activity than the cis molecule. These findings can be explained by viewing the biological activities of compounds such as 1 as the interaction of the vasopressin receptor with a number of discrete molecular entities, conformers of 1, which present different pharmacophores. Models have been developed to assist in the understanding of these results.
authors.affiliation: Department of Peptide Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406.
authors.forename: W F
authors.initials: WF
authors.lastname: Huffman
authors.forename: C
authors.initials: C
authors.lastname: Albrightson-Winslow
authors.forename: B
authors.initials: B
authors.lastname: Brickson
authors.forename: H G
authors.initials: HG
authors.lastname: Bryan
authors.forename: N
authors.initials: N
authors.lastname: Caldwell
authors.forename: G
authors.initials: G
authors.lastname: Dytko
authors.forename: D S
authors.initials: DS
authors.lastname: Eggleston
authors.forename: L B
authors.initials: LB
authors.lastname: Kinter
authors.forename: M L
authors.initials: ML
authors.lastname: Moore
authors.forename: K A
authors.initials: KA
authors.lastname: Newlander
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000595:Amino Acid Sequence; D000818:Animals; D001127:Arginine Vasopressin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D001681:Biological Assay; D001769:Blood; D055598:Chemical Phenomena; D002621:Chemistry; D004285:Dogs; D006801:Humans; D007679:Kidney Medulla / Q000201:enzymology; D008968:Molecular Conformation; D009994:Osmolar Concentration; D051381:Rats; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism; D017483:Receptors, Vasopressin; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013552:Swine; D014556:Urine; D014667:Vasopressins / Q000037:antagonists & inhibitors*
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D011945:Receptors, Angiotensin; D017483:Receptors, Vasopressin; D014667:Vasopressins; D001127:Arginine Vasopressin; C050890:1-((beta-mercapto-beta)beta cyclopentamethylenepropionic acid)-2-(O-ethyl-Tyr)-4-Val-9-des-Gly-arginine vasopressin