title: Conformational effects on the activity of drugs. 13. A revision of previously proposed models for the activation of alpha- and beta-adrenergic receptors.
abstract: The alpha 1-, alpha 2-, beta 1-, and beta 2-adrenergic properties of the 2-(3,4-dihydroxyphenyl)morpholines 3 and 4 (2-DPMs), of the 3-(3,4-dihydroxyphenyl)-3-piperidinols 5 and 6 (3-DPPs), and of the trans-2-amino-5,6-dihydroxytetrahydronaphthalen-1-ols 7 and 8 and the trans-2-amino-6,7-dihydroxytetrahydronaphthalen-1-ols 9 and 10 (2-ADTNs) were evaluated in vitro both by radioligand binding assays and by functional tests on isolated preparations and compared with those of norepinephrine (NE, 1) and isoprenaline (ISO, 2). Through a comparison of the stereostructures of the compounds examined with their biopharmacological properties, it was possible to revise previously proposed molecular models for the direct activation of alpha- and beta-adrenergic receptors. The revised models (A-C) provided information about the conformational requirements of adrenergic drugs, which substantially fit in with the results of several published studies involving conformationally-restricted adrenoceptor agonists. The different position of the catecholic hydroxyl groups in model B, which refers to the alpha 2 receptors, and in model C, which refers to the beta receptors, confirms the importance of the rotameric position of the aromatic ring of catecholamines in the interaction with the alpha- and beta-adrenergic receptor.
authors.affiliation: Istituto di Chimica Farmaceutica e Tossicologica, Università di Pisa, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Macchia
authors.forename: A
authors.initials: A
authors.lastname: Balsamo
authors.forename: M C
authors.initials: MC
authors.lastname: Breschi
authors.forename: A
authors.initials: A
authors.lastname: Lapucci
authors.forename: A
authors.initials: A
authors.lastname: Lucacchini
authors.forename: F
authors.initials: F
authors.lastname: Macchia
authors.forename: C
authors.initials: C
authors.lastname: Manera
authors.forename: A
authors.initials: A
authors.lastname: Martinelli
authors.forename: C
authors.initials: C
authors.lastname: Martini
authors.forename: E
authors.initials: E
authors.lastname: Martinotti
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002417:Cattle; D006168:Guinea Pigs; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects* / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013566:Sympathomimetics / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D008024:Ligands; D011942:Receptors, Adrenergic, alpha; D011943:Receptors, Adrenergic, beta; D013566:Sympathomimetics