title: Novel cyclic analogs of angiotensin II with cyclization between positions 5 and 7: conformational and biological implications.
abstract: To study the conformational features of molecular recognition of angiotensin II (Asp1-Arg2-Val3-Tyr4-Val/IIe5-His6-Pro7-Phe8, AII), the synthesis and biological testing of several cyclic analogs of AII cyclized between positions 5 and 7 have been performed. The synthesized analogs were Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Pen7)-Phe8 (3), Sar1-Arg2-Val3-Tyr4-cyclo(Asp5-His6-Apt7)-Phe8 (4), Sar1-Arg2-Val3-Tyr4-cyclo(Glu5-His6-Apt7)-Phe8 (5), Sar1-Arg2-Val3-Tyr4-cyclo-(Cys5-His6-Mpt7)-Phe8 (6), Sar1-Arg2-Val3-Tyr4-cyclo(Cys5-His6-Mpc7)-Phe8 (7), Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpt7)-Phe8 (8), and Sar1-Arg2-Val3-Tyr4-cyclo(Hcy5-His6-Mpc7)-Phe8 (9), where Apt stands for 4-amino-trans-proline, and Mpt and Mpc for 4-mercapto-trans- and -cis-prolines, respectively. Compound (9) showed good affinity at AT-1 receptors, namely a KD = 20 nM. In functional assays, it showed the characteristics of a weak partial agonist with a relative affinity of 0.26% of that for AII and an intrinsic efficacy, alpha E, of 0.42. Molecular modeling suggested a possible explanation for this finding: the relatively strong binding and the weak partial agonistic activity of compound 9 are due to interaction with AT-1 receptor of only two functionally important groups, namely, the side chains of the His6 and Phe8 residues.
authors.affiliation: Department of Molecular Biology and Pharmacology, Washington University, St.Louis, Missouri 63130, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Zhang
authors.forename: G V
authors.initials: GV
authors.lastname: Nikiforovich
authors.forename: J
authors.initials: J
authors.lastname: Pérodin
authors.forename: D E
authors.initials: DE
authors.lastname: Richard
authors.forename: E
authors.initials: E
authors.lastname: Escher
authors.forename: G R
authors.initials: GR
authors.lastname: Marshall
mesh_terms: D000595:Amino Acid Sequence; D000804:Angiotensin II / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009119:Muscle Contraction; D011487:Protein Conformation; D011817:Rabbits; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D014662:Vasoconstrictor Agents; D000804:Angiotensin II