Conformationally restrained analogs of sympathomimetic catecholamines. Synthesis, conformational analysis, and adrenergic activity of isochroman derivatives.
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.
Macchia
B
B
Istituto di Chimica Farmaceutica e Tossicologica, Università di Pisa, Italy.
Balsamo
A
A
Breschi
M C
MC
Chiellini
G
G
Lapucci
A
A
Macchia
M
M
Manera
C
C
Martinelli
A
A
Martini
C
C
Scatizzi
R
R
D000818:Animals; D002395:Catecholamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006168:Guinea Pigs; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009130:Muscle, Smooth / Q000187:drug effects; D009638:Norepinephrine / Q000031:analogs & derivatives*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013566:Sympathomimetics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
D002395:Catecholamines; D013566:Sympathomimetics; D009638:Norepinephrine