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Biomedical subjects

J Hynes

Publications and source records attributed to J Hynes.

8 recordsLinked to original sources
PubMed1998

Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis.

We show that carbohydrates constitute an attractive source of readily available, stereochemically defined scaffolds for the facile attachment of side chains contained in genetically encoded and other amino acids. beta-D- and beta-L-glucose, L-mannose, and the 6-deoxy-6-N-analogue of beta-D-glucose have been employed to synthesize peptidomimetics that bind the SRIF receptors on AtT-20 mouse pituitary cells, five cloned human receptor subtypes (hSSTRs), and the NK-1 receptor. The affinity profile of various sugar-based ligands at the hSSTRs is compared with that of SRIF. Compound 19 bound hSSTR4 with a Ki of 100 nM. Subtle structural changes affect affinities. Evidence is presented that suggests that one compound (8) binds both the AtT-20 cell receptors and the five hSSTRs via a unique mode. The SARs of the glycosides at SRIF receptors differ markedly from those at the NK-1 receptor. For example a 4-benzyl substituent is important for SRIF receptor binding, but the 4-desbenzyl analogue 27 was highly potent (IC50 of 27 nM) at the NK-1 receptor. A new, nonbasic method for the synthesis of base-sensitive ethers from primary and secondary alcohols is also described.

Animals↗
PubMed1996

Synthesis of potent cyclic hexapeptide NK-1 antagonists. Use of a minilibrary in transforming a peptidal somatostatin receptor ligand into an NK-1 receptor ligand via a polyvalent peptidomimetic.

The endogenous peptides somatostatin (SRIF) and substance P comprise very different structures. Although both bind G-protein-coupled receptors, the SRIF receptors (SSTR 1-5) recognize SRIF and related peptides which retain its beta-turn such as the potent cyclic hexapeptide SRIF agonist L-363,301 (6a), but not substance P. Conversely the NK-1 receptor binds substance P but not the above ligands. In contrast, the beta-D-glucosides 1 and 2, designed to mimic the beta-turn of 6a, bind both receptors. This observation led us to attempt the conversion of 6a into the first potent, selective cyclic hexapeptide ligand for the NK-1 receptor. To this end, we combined design with a minilibrary approach. The goal was accomplished with surprising ease, leading to the NK-1 receptor antagonist 9 (IC50 2.0 +/- 0.4 nM). This demonstrates that peptidomimetics, incorporating in this case the promiscuous beta-D-glucose scaffold, can provide valuable clues about receptor similarities not revealed by their endogenous ligands. In addition, this work suggests that the use of libraries and rational design need not be mutually exclusive approaches to lead discovery.

Amino Acid Sequence↗
PubMed1990

Multiple-sited (heterotopic) pregnancy after in vitro fertilization and gamete intrafallopian transfer.

Pregnancies occurring simultaneously in different body sites (heterotopic pregnancies) are a rare condition thought to occur in 1 of 30,000 spontaneous pregnancies. Individual cases may occur after in vitro fertilization (IVF) or gamete intrafallopian transfer (GIFT). In the past 4 1/2 years, our unit has performed 6,204 IVF/GIFT or pronuclear stage transfer cycles of treatment. Ten such pregnancies proven by surgical, ultrasound, and histological diagnosis have occurred. In the same period 640 IVF, 355 GIFT, and 6 pronuclear stage transfer clinical pregnancies were achieved. This suggests that the incidence of heterotopic pregnancy after assisted reproduction is closer to 1 of 100 pregnancies. Clinicians managing early complications of IVF, GIFT, and/or pronuclear stage transfer pregnancies should be aware of this relatively high incidence of concomitant intrauterine and extrauterine pregnancy.

Female↗
PubMed1989

Synergy between 5,10-dideaza-5,6,7,8-tetrahydrofolic acid and methotrexate in mice bearing L1210 tumors.

In vivo studies with 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF), an inhibitor of glycinamide ribonucleotide transformylase, indicate that at doses ranging from 2.5 to 10 mg/kg, it prolongs the survival of mice implanted with L1210 tumors. Lower doses of this agent have no effect. Parallel studies with methotrexate indicate that DDATHF is not as potent or as efficacious as methotrexate in this animal model. Low doses of DDATHF combined with low doses of methotrexate can cause a significant increase in the survival of L1210 tumor-bearing mice, suggesting synergism between these two antifolates.

Animals↗
PubMed1979

Purification of mammalian tumor (L1210) thymidylate synthetase by affinity chromatography on stable biospecific adsorbent. Stabilization of the enzyme with neutral detergents.

Thymidylate synthetase from mouse leukemic L1210 cells was purified to electrophoretic homogeneity with 70% yield as a result of an affinity chromatography procedure based on reversible deoxyuridylate-dependent binding of the enzyme to a stable biospecific adsorbent, 10-formyl-5,8-dideazafolate, immobilized on aminoethyl-Sepharose. The presence of neutral detergents, Triton X-100, or Nonidet P40 stabilized thymidylate synthetase during purification. Analytical electrophoresis of the enzyme treated with an excess of 5-fluorodeoxyuridylate and 5,10-methylenetetrahydrofolate showed the presence of two forms of thymidylate synthetase--5-fluorodeoxyuridylate.5,10-methylenetetrahydrofolate complex, indicating that there are two binding sites for 5-fluorodeoxyuridylate present on the enzyme molecule. Molecular weight of native thymidylate synthetase was found to be 75,000, whereas that for the monomer was 38,500.

Animals↗
PubMedDate not supplied

Study on the mechanisms of glucocorticoid-induced hypertension: glucocorticoids increase transmembrane Ca2+ influx in vascular smooth muscle in vivo.

Blood pressure (BP) and ex vivo influx rate of Ca2+ in excised aortae were measured in rabbits implanted with silastic rubber strips impregnated with glucocorticoids (GC) [dexamethasone (DEX) or cortisol (FK)], or carbenoxolone (CX) [inhibitor of 11 beta-hydroxysteroid dehydrogenase (11-HSD), in a large (lg) or a small (sm) (10 times smaller) concentration], or FK plus CX (sm), or DEX plus RU 38486 (a specific GC-receptor blocker). After 4-6 weeks rabbits implanted with DEX, CX (lg), and FK+CK (sm) developed hypertension. Those implanted with FK alone (yielding physiological serum concentration of FK), CX (sm), and DEX+RU 38486 did not develop hypertension. Rates of unidirectional influx of Ca2+ measured in rings of excised aortae were in all hypertensive rabbits more than twice those in the control rabbits (implanted with silastic strips not containing any steroids). In all normotensive rabbits, Ca2+ influx rates remained normal. We conclude that, in analogy with the in vitro findings in cultured vascular smooth muscle (VSM) cells treated with GC, also in vivo, the elevation of tissue levels of GC causes an increase in the influx rate of Ca2+ in VSM. We propose that this may be the main pathogenic mechanism of GC-induced hypertension.

Animals↗