Tetrahydroisoquinolines as dopaminergic ligands: 1-Butyl-7-chloro-6-hydroxy-tetrahydroisoquinoline, a new compound with antidepressant-like activity in mice.
International audience; Three series of 1-substituted-7-chloro-6-hydroxy-tetrahydroisoquinolines (1-butyl-, 1-phenyl- and 1-benzyl derivatives) were prepared to explore the influence of each of these groups at the 1-position on the affinity for dopamine receptors. All the compounds displayed affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, and were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. Different structure requirements have been observed for adequate D(1) or D(2) affinities. This paper details the synthesis, structural elucidation, dopaminergic binding assays, structure-activity relationships (SAR) of these three series of isoquin…
1,2-Dipolar addition model for the cytoprotective activity of selected α,β-unsaturated compounds with CO functionality: an ab initio study
Abstract The mechanism of the addition of a nucleophile (an alkylthiol group) to a double bond of α,β-unsaturated systems in the gas phase was explored. In this study, intermediates of the reaction were also investigated using ab initio calculations (RHF/6-31G ∗ and MP2/6-31+G ∗ ). Our results indicate that direct dipolar attack of the S–H group of an alkylthiol on the CC double bond is a reasonable reaction path. The present results represent, therefore, additional support for our hypothesis. This suggests that the mechanism of cytoprotection might be mediated, at least in part, by a reaction between the olefinic acceptor and the sulfhydryl-containing groups of the mucosa.
New antitumoral acetogenin ‘Guanacone type’ derivatives: Isolation and bioactivity. Molecular dynamics simulation of diacetyl-guanacone
We describe herein the isolation and semisynthesis of four acetogenin derivatives (1-4) as well as their ability to inhibit the mitochondrial respiratory chain and several tumor cell lines. In addition, four nanoseconds (ns) of MD simulation of compound 4, in a fully hydrated POPC bilayer, is reported.
Structure-activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives
Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D(1)-like and/or D(2)-like dopamine receptors in striatal membranes, although they were unable to inhibit [(3)H]-dopamine uptake in striatal synaptosomes. The halogen placed on the benzylic ring in 1-benzyl-THIQs, compounds of the series 1, 2'-bromobenzyl derivatives with K(i) values into the nanomolar range, and the series 2, 2',4'-dichlorobenzyl-THIQ homologues, proves to be an important factor to modulate affinity at dopamine receptor. (C) 2009 Elsevier Masson SAS. All ri…
Efficient synthesis and structural analysis of new dioxopiperazine isoquinolines
Abstract We report herein the synthesis of new dioxopiperazine isoquinolines using the Pictet–Spengler cyclisation. Our synthetic strategy for the preparation of two new compounds ( 5 , 6 ), with a tetrahydro-6H-pyrazino[1,2-b]isoquinoline-1,4-dione moiety was developed in only four steps. To understand better the crucial step of the synthesis reported here, theoretical calculations using semiempirical (PM3), ab initio and DFT computations were carried out on a reduced system model. The structure of chlorohydrate water solvate of tetrahydro (2-piperidinylethyl)-6H-pyrazino [1,2-b]isoquinoline-1,4-dione ( 6·HCl·2H2O ) was determined by X-ray diffraction. Theoretical calculations (RHF/3-21G a…
Molecular recognition and binding mechanism of N-alkyl-benzyltetrahydroisoquinolines to the D1 dopamine receptor. A computational approach
Fil: Suvire, Fernando Daniel. Consejo Nacional de Investigaciones Cientificas y Tecnicas; Argentina. Universidad Nacional de San Luis. Facultad de Quimica, Bioquimica y Farmacia; Argentina
Polycerasoidol, a Natural Prenylated Benzopyran with a Dual PPARα/PPARγ Agonist Activity and Anti-inflammatory Effect
Dual peroxisome proliferator-activated receptor-α/γ (PPARα/γ) agonists regulate both lipid and glucose homeostasis under different metabolic conditions and can exert anti-inflammatory activity. We investigated the potential dual PPARα/γ agonism of prenylated benzopyrans polycerasoidol (1) and polycerasoidin (2) and their derivatives for novel drug development. Nine semisynthetic derivatives were prepared from the natural polycerasoidol (1) and polycerasoidin (2), which were evaluated for PPARα, -γ, -δ and retinoid X receptor-α activity in transactivation assays. Polycerasoidol (1) exhibited potent dual PPARα/γ agonism and low cytotoxicity. Structure–activity relationship studies revealed th…
Conformational study of N-alkyl-benzyltetrahydroisoquinolines alkaloid
Abstract An exhaustive conformational study on the benzyltetrahydroisoquinolines (BTHIQ) from ab initio (RHF/6-31G(d)) calculations was carried out. The effects of different substituents at chiral C 1 atom were also considered. Our results indicate that different substituents at C 1 in BTHIQ molecules introduce a significant steric hindrance which, in turn, might be responsible for a conformational restriction favouring or disfavouring the spatial orientation of the lone pairs of N atom allowing or not the electronic attachment with the side chain of Asp residue. These results can serve as an aid for designing suitable structures of BTHIQs for better dopamine D 1 -receptor inhibitory activi…