Topographic probes of angiotensin and receptor: potent angiotensin II agonist containing diphenylalanine and long-acting antagonists containing biphenylalanine and 2-indan amino acid in position 8

Abstract

A series of phenylalanine-mimicking amino acids with increasing conformational restraint were prepared and incorporated into angiotensin II, in order to develop topographic probes of angiotensin useful for probing receptor boundaries by molecular graphics analysis and for conformational analysis of the ligand by NMR. In binding studies, all analogues displayed high affinity for rat uterus (K¡ of 0.74-6.08 nM) and brain (0.46-1.82 nM) receptors. In smooth muscle (rat uterus) contraction assay, the diphenylalanine-containing [Sar1,Dip8]AII and [Sar1,D-Dip8]AII were potent agonists with respectively 284% and 48% activity of [Asn^AII. In contrast, the biphenylalanine-containing [Sar1,Bip8]AII, [Sar1,D-Bip8]AII, and the 2-indan amino acid containing [Sar1,2-Ind8]AII were potent inhibitors, approximately 9, 2, and 1.4 times more effective than a standard antagonist, [SaP.Leu^AII. Their respective pA10 values in rat uterus assay were 8.87, 8.70, and 8.82. By comparison, the pA10 value for [Sar1,Leu8]AII was 8.36. In rats, a single dose of 10 µ% of [Sar1,2-Ind8]AII or [Sar1,Bip8]AII produced prolonged blockade of the pressor response toward angiotensin II for over 90 min. The very different pharmacological profiles of these rigid aromatic analogues suggest that the angiotensin receptor activation site consists of a relatively wide and elongated pocket with a narrow opening.The discovery that the endogenous opioid, enkephalin, binds to morphine receptor1"1

Central and peripheral actions of a nonpeptidic angiotensin II receptor antagonist.

“…These functional data are complemented by receptor binding data showing that, relative to [Asn']Ang II or [Ile 5 ]Ang II, the binding affinity of [Sar']Ang II-(l-7) NH 2 ([Sar\Pro, desPhe^Ang II) in the brain was 5,000 -fold lower but in the uterus was only 10-30-fold lower. 19 In contrast, Ang-(l-7) was without biological activity in peripheral tissues but stimulated the release of vasopressin from hypothalamoneurohypophysial brain tissue. 20 Together, these data support the possibility that differences exist between central nervous system and peripheral tissue Ang II receptor populations.…”

Cyclic and linear bradykinin analogues: implications for B2 antagonist design

“…The [ Hyp 3 ,D‐Phe 7 ]‐BK elicited a greater pA 2 of 5.6 on ileum, with less agonistic activity (0.4%) on uterus (13). The [ Thi 5 , 8 ,D‐Phe 7 ]‐BK showed a > 20‐fold improvement over [D‐ Phe 7 ]‐BK, and gave the respective pA 2 of 6.3 and 6.4 on ileum and uterus (40). c.…”

Position Three in Vasopressin Antagonist Tolerates Conformationally Restricted and Aromatic Amino Acid Substitutions: A Striking Contrast with Vasopressin Agonists

“…The [b-(benzylthio)-b,b-cyclopentamethylenepropionic acid [75], 2-aminoindan-2-carboxylic acid (Aic) [49,54], Boc-Aic [53], D,L-2-aminotetralin-2-caboxylic acid (Atc) [45,49] and Boc-D,L-Atc [48] were synthesized in this laboratory using routine procedures. For both Aic and D,L-Atc the spirohydantoin version of the Strecker synthesis [51,52] was applied.…”

“…These studies raised the intriguing, if somewhat remote, possibility that a Pro 3 = Tic 3 interchange might be tolerated in (B) with retention of V 2 antagonism. The conformationally restricted amino acids Oic, Atc and Aic have been shown to be valuable tools in the design of enzyme inhibitors and of antagonists of some peptide hormones [39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54]. To date, Oic, Atc and Aic have not been employed in the design of AVP or OT antagonists.…”