Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis and adrenergic activity of isochroman derivatives

Abstract

In previous papers dealing with the study of the conformations and the biopharmacological activity of conformationally restrained analogs of sympathomimetic catecholamines (NE and ISO), proposals were advanced for the three-dimensional molecular models A, B, and C; these models provided information about the steric requirements for the direct activation of alpha 1, alpha 2,beta 1, and beta 2 adrenoceptors, respectively. The 1-(aminomethyl)-6,7-dihydroxyisochromans 11 and 12 and the 1-(aminomethyl)-5,6-dihydroxyisochromans 13 and 14 (1-AMDICs) are two different types of semirigid analogs of NE and ISO. The alpha 1, alpha 2, beta 1, and beta 2 adrenergic properties of the 1-AMDICs 11-14 were evaluated in vitro, both by radioligand binding assays and by functional tests on isolated preparations, and were compared with those of their parent compounds (NE and ISO). The results of a conformational study carried out by means of both 1H NMR spectrometry and theoretical calculations indicated that, in these 1-AMDICs, the presumed active groups (aryl moiety, amine nitrogen and benzylic ethereal oxygen) are in a spatial relationship corresponding to the one found for NE and ISO in their preferred conformations, which also proved to be the pharmacophoric conformation in the models A-C. By means of a comparison of the stereostructures of the 1-AMDICs 11-14 with their biopharmacological properties, it was possible to obtain a further definition of the model B with respect to the activation of the alpha 2 adrenoceptors; the superimposition of the 1-AMDICs 11 and 12 with the molecular model C made it possible to detect an area of the beta-adrenergic receptors which might hinder the fit of adrenergic drugs that are analogs of catecholamines with these receptors.

Ligand-Dependent Perturbation of the Conformational Ensemble for the GPCR β2 Adrenergic Receptor Revealed by HDX

“…Average % deuterium uptake differences between apo-β 2 AR and each of the ligand complexes are shown for the 10 second time point only with their propagated standard errors. Dissociation constants from the literature are listed under each ligand: Isoproterenol(Macchia, Balsamo et al 1993; Gether, Lin et al 1995), Clenbuterol(Torneke, Ingvast Larsson et al 1998), Alprenolol and Timolol (Baker 2005) and Carazolol(Heald, Jeffs et al 1983; Zheng, Berridge et al 1994). Peptides with average % D uptake differences ranging from −5% to −3% and 3 to 5% were subjected to an unpaired one-tailed t test to determine if differences were significant, otherwise % D differences are color coded according to the key (white indicates no significant change).…”

Agonists and Antagonists Targeting the Different α2-Adrenoceptor Subtypes

“…49) [122], and isochromane (e.g. 50) [123] derivatives maintain a good α 2 -stimulating activity; obviously, the response (potency and selectivity) depends on the position and the nature of the substituents on the aryl ring and/or on the nitrogen atom.…”

N-n-Propyl-Substituted 3-(Dimethylphenyl)piperidines Display Novel Discriminative Properties between Dopamine Receptor Subtypes: Synthesis and Receptor Binding Studies

“…α 2 -Receptor binding assays were performed in rat cerebral cortex membranes, as elsewhere reported. , The values of inhibition constants ( K i , nM) were calculated from the respective IC 5 0 values by applying the Cheng−Prusoff equation…”

“…Ki values were obtained from IC50 by the Cheng-Prusoff equation: 31 R2-Receptor binding assays were performed in rat cerebral cortex membranes, as elsewhere reported. 32,33 The values of inhibition constants (Ki, nM) were calculated from the respective IC50 values by applying the Cheng-Prusoff equation. 31 [ 3 H]Rauwolscine was used as the radioligand at a concentration of 2.0 nM.…”