Structure-activity relationships on adrenoceptors and imidazoline-preferring binding sites (I(1,2)-PBSs). Part 1: Weak intramolecular H-bond and conformational flexibility in a new I1-PBS-selective imidazoline analogue, trans1-(4',5'-dihydro-1'H-imidazol-2'-yl)methyl-2-hydroxyindane (PMS 952).

in Bioorganic & Medicinal Chemistry (2000), 8(8), 1861-9

The highly selective I1-PBS imidazoline analogue PMS 952 has been selected to study the incidence of intramolecular hydrogen bond and molecular flexibility on its biological activity. On one hand, the ... [more ▼]

The highly selective I1-PBS imidazoline analogue PMS 952 has been selected to study the incidence of intramolecular hydrogen bond and molecular flexibility on its biological activity. On one hand, the weak energy difference between three calculated conformers does not support the stabilization of one conformer by an internal hydrogen bond. The 3-D electrostatic map confirms this feature and the solvent effect does not significantly modify the relative energy of these conformers. On the other hand, the conformational spaces of the neutral and ionized forms present a great number of equilibrium structures, in a short energetic range (20 Kcal). The results are representative of an exceptional conformational flexibility due to a cooperative effect between several parts of the molecule. [less ▲]

Design and synthesis of imidazoline derivatives active on glucose homeostasis in a rat model of type II diabetes. 1. Synthesis and biological activities of N-benyl-N'-(arylalkyl)-2-(4',5'-dihydro-1'H-imidazol-2'-yl) piperazines

in Journal of Medicinal Chemistry (1997), 40(23), 3793-3803

Design and modeling of new platelet-activating factor antagonists.3. Relative importance of hydrophobicity and electronic distribution in piperazinic series

in Journal of Lipid Mediators and Cell Signalling (1996), 15(2), 161-173

Design and modeling of new PAF antagonists - 1,4-bis-(3',4',5'-trimethoxybenzoyl)-2-substituted carbonyloxymethyl piperazines

in Journal of Lipid Mediators and Cell Signalling (1994), 10(1-2), 153-154

Paf-Receptor. iii. Conformational and Electronic Properties of Paf-Like Agonists and Antagonists

in Biochimica et Biophysica Acta (1991), 1085(1), 91-105

In order to compare electronic and conformational properties of PAF-agonists and PAF-antagonists, 14 analogues structurally related to PAF were studied. A common conformation of the glycerol backbone was ... [more ▼]

In order to compare electronic and conformational properties of PAF-agonists and PAF-antagonists, 14 analogues structurally related to PAF were studied. A common conformation of the glycerol backbone was present in all agonists and all constrained or flexible antagonists. The distinction between agonists and antagonists appears to be casted on position-2 where the folded conformation of the substituent for agonists should be the most probable. In position-3 the gauche conformation can be adopted by all the analysed compounds. The electrostatic potential well at -30 kcal/mol stretches to the carbonyl group in position-2 in the folded conformation of the agonists. On the contrary, in constrained antagonists, a second negative zone appears around the carbamate group. Given the modelling results, the triethylammonium PAF analogue considered in literature as a weak agonist, was resynthesized and proved to be more potent than previously reported. These experimental results confirm our hypothesis in terms of a common conformation of agonist and antagonist PAF-like molecules. [less ▲]

PAF receptor and cache-oreilles effect. Simple PAF antagonists

in Lipids (1991), 26(12), 1167-1171

Paf-Receptor. 1. 'Cache-Oreilles' Effect of Selected High-Potency Platelet-Activating Factor (Paf) Antagonists

in Journal of Lipid Mediators (1989), 1(4, Jul-Aug), 201-15

Three-dimensional electrostatic maps were calculated for six potent antagonists of platelet-activating factor (PAF), the antagonists being selected for their apparent structural heterogeneity. The ... [more ▼]

Three-dimensional electrostatic maps were calculated for six potent antagonists of platelet-activating factor (PAF), the antagonists being selected for their apparent structural heterogeneity. The molecules examined were the compact Ginkgolides BN 52020, BN 52021 and BN 52022 (1, 2 and 3), the semi-rigid kadsurenone (4), a flexible synthetic dinor type C furanoid lignan L-652,731 (5a) and the triazolothienobenzodiazepine WEB 2086 (7). Calculation of the electrostatic potential generated around all the above molecules showed the existence of two wells of negative potential or 'cache-oreilles' (ear-muffs), i.e., the isocontours drawn at -10 kcal/mol, located at 180 degrees from each other and separated by a maximum distance of 22-27 A. Except for the synthetic dinor type C furanoid lignan (5a), the molecules also presented a moderate hydrophobic fragment, which constitutes a third point of interaction with the high-affinity binding site in rabbit and human platelets. The findings of the present study allow speculation that this high-affinity acceptor site may be a 'polarized cylinder' with a diameter of 10-12 A. [less ▲]