Leptin-mediated inhibition of the insulin-stimulated increase in fatty acid uptake in differentiated 3T3-L1 adipocytes.

The effects of insulin and leptin on fatty acid uptake in differentiated (adipocytes) and undifferentiated 3T3-L1 cells were investigated. It was demonstrated that in undifferentiated 3T3-L1 cells, insulin and leptin have no effect on fatty acid uptake. In differentiated 3T3-L1 adipocytes, insulin had a concentration-dependent stimulatory effect on fatty acid uptake, whereas leptin on its own had no effect.

PD 176252--the first high affinity non-peptide gastrin-releasing peptide (BB2) receptor antagonist.

In this paper we describe the development of a novel series of non-peptide, "balanced" neuromedin-B preferring (BB1)/gastrin-releasing peptide preferring (BB2) receptor ligands as exemplified by PD 176252. PD 176252, which exhibits nanomolar affinity for both the BB1 (Ki = 0.15 nM) and BB2 (Ki = 1.

Quantitative structure-activity relationships (QSARs) of N-terminus fragments of NK1 tachykinin antagonists: a comparison of classical QSARs and three-dimensional QSARs from similarity matrices.

The ability of three-dimensional quantitative structure-activity relationships (QSARs) derived from classical QSAR descriptors and similarity indices to rationalize the activity of 28 N-terminus fragments of tachykinin NK1 receptor antagonists was examined. Two different types of analyses, partial least squares and multiple regression, were performed in order to check the robustness of each derived model. The models derived using classical QSAR descriptors lacked accurate quantitative and predictive abilities to describe the nature of the receptor-inhibitor interaction.

Rational design of high affinity tachykinin NK1 receptor antagonists.

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand).

Conformationally restricted analogues of the potent CCK-B antagonist CI-988.

The synthesis and structure-activity relationships (SAR) for a series of conformationally restricted analogues of the selective cholecystokinin (CCK) antagonist CI-988 and some closely related analogues are described. A series of appropriately substituted cis- and trans-amino decalins are prepared that mimic the through bond distances between the functional groups in the parent compound CI-988 whilst restricting bond rotation. This strategy has led to conformationally more rigid derivatives that have increased CCK-B receptor binding affinity.