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M A Lago

Publications and source records attributed to M A Lago.

9 recordsLinked to original sources
PubMed1999

Orally bioavailable nonpeptide vitronectin receptor antagonists containing 2-aminopyridine arginine mimetics.

A peptide RGD analog containing a novel 2-aminopyridine arginine mimetic was discovered to have good affinity and selectivity for the vitronectin receptor. Incorporation of the 2-aminopyridine arginine mimetic into the 3-oxo-1,4-benzodiazepine-2-acetic acid integrin antagonist series led to novel and potent nonpeptide vitronectin receptor antagonists with promising levels of oral bioavailability.

Administration, Oral↗
PubMed1994

Lysine 182 of endothelin B receptor modulates agonist selectivity and antagonist affinity: evidence for the overlap of peptide and non-peptide ligand binding sites.

The potent vasoactive peptide hormone endothelin (ET) binds to receptors which belong to the G-protein coupled receptor family. The availability of non-peptide antagonists for ET receptors allows investigation of the relationship among the binding sites for peptide and non-peptide ligands. In this study, a lysine residue, conserved within transmembrane domain 3 (TM3) of the ETA and ETB receptor subtypes, is implicated in agonist and antagonist binding by its analogous position within TM3 to a binding site aspartate residue conserved within bioactive amine receptors. Replacement of this lysine within hETB by arginine, alanine, methionine, aspartate, or glutamate results in hETB variants with unaltered affinities for agonist peptide ET-1 but which have affinities for peptide agonists ET-2, ET-3, sarafotoxin 6C, and TRL 1736 which are between 1-3 orders of magnitude lower than their corresponding wild-type hETB values. Significantly, the affinities of non-peptide antagonists, (+/-)-SB 209670 and its analogs as well as Ro 46-2005, are abrogated. The results suggest that an interaction of K182 of hETB with the indan 2-carboxyl of (+/-)-SB 209670 may contribute to the high-affinity binding of the diarylindan antagonists. The results indicate that TM3 of hETB is a region of overlap among the binding sites of non-peptide antagonists and the affected peptide agonists.

Amino Acid Sequence↗
PubMed1994

Conformationally constrained peptides and semipeptides derived from RGD as potent inhibitors of the platelet fibrinogen receptor and platelet aggregation.

Structure-activity studies have been pursued on cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-Pen]-NH2, 2 (SK&F 106760), a potent inhibitor of platelet aggregation, in an effort to improve potency and affinity for the GPIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produced a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modification by replacing the disulfide tether N alpha-acetylcysteine/penicillamineamide with the novel, inexpensive, achiral, constrained, and more lipophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-[Mba-(N alpha-Me)Arg-Gly-Asp-Man], 18 (SK&F 107260), which exhibited significant enhancement in both affinity and potency. To further investigate the effect of the phenyl ring at the C-terminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcysteines were synthesized, which culminated in the cyclo-S,S-[Ac-Cys-(N alpha-Me)Arg-Gly-Asp-(2R,3S)-beta-phenylCys]-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constrained cyclic disulfide ring to probe the stereochemical and steric requirements for receptor interaction.

Amino Acid Sequence↗
PubMed1994

Nonpeptide endothelin receptor antagonists. I. Effects on binding and signal transduction on human endothelinA and endothelinB receptors.

The effect of a series of endothelin (ET) receptor antagonists, including the novel nonpeptide receptor antagonist, SB 209670, on [125I]ET-1 binding to human ET receptors (ETA and ETB) cloned and stably expressed in Chinese hamster ovary cells was studied. SB 209670 was found to compete for [125I]ET-1 binding with apparent Ki values of 0.43 +/- 0.09 and 14.7 +/- 3.0 nM for ETA and ETB receptors, respectively. This inhibition was competitive because addition of SB 209670 in saturation binding experiments resulted in decreased affinity, with no change in maximum binding. In addition, SB 209670 inhibited ET-1-mediated accumulation of inositol phosphates and intracellular calcium release in a concentration-dependent manner. The racemic mixtures, (+/-)-SB 209670 and (-)-SB 209670, were approximately 1.5 and at least 200-fold less potent than SB 209670. The binding affinity of (+/-)-SB 209670 therefore resides in (+)-antipode. The peptide antagonists, BQ123 (ETA-selective) and RES 701 (ETB-selective), were 40- and 6-fold less potent than SB 209670 in inhibition of [125I] ET-1 binding to ETA and ETB receptors, respectively. The nonselective peptide antagonist, PD 142893, was 75- and 10-fold less potent than SB 209670, whereas the nonpeptide antagonist, bosentan, was approximately 80- and approximately 30-fold less potent than SB 209670 in inhibition of [125I]ET-1 binding to ETA and ETB receptors, respectively. Thus, the present studies indicate clearly that SB 209670 is the most potent nonpeptide ET receptor antagonist yet described.

Animals↗
PubMed1994

Nonpeptide endothelin receptor antagonists. II. Pharmacological characterization of SB 209670.

The pharmacological characterization of SB 209670, a highly potent nonpeptide endothelin ETA/ETB receptor antagonist was performed. SB 209670 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in the isolated rat aorta (ETA receptor-mediated vascular contraction). The Kb for inhibition of ETA receptor-mediated contraction by SB 209670 was 0.4 +/- 0.04 nM. Inhibition by SB 209670 was stereoselective as the (+)-antipode of SB 209670 was approximately 575-fold more potent than the (-)-antipode. Relative to other ET receptor antagonists, the potency of SB 209670 for inhibiting ETA receptor-mediated vascular contraction was 45-, 180- and 775-fold more potent than the ETA selective antagonist BQ-123, or the mixed ETA/ETB receptor antagonists bosentan or PD142893, respectively. The pharmacological antagonism produced by SB 209670 was specific for ET-1. SB 209670 inhibited ETB receptors in the isolated rabbit pulmonary artery as demonstrated by concentration-dependent, parallel rightward shifts in either the ET-1 or sarafotoxin S6c (S6c) concentration-response curves. The Kb values for inhibition were 200 +/- 9 and 52 +/- 14 nM for ET-1 and S6c, respectively. In contrast, neither the ETB selective antagonist RES-701 (10 microM) nor BQ-123 (10 microM) inhibited S6c-mediated vasoconstriction. However, PD 142893 (10 microM) and bosentan (10 microM) produced a small rightward shift in the S6c concentration-response curve, each with Kb values of 1.5 to 3.7 microM. In isolated human circumflex coronary arteries, (+/-)-SB 209670 inhibited ET-1 mediated contraction with a Kb value of 7 +/- 3 nM.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗