title: Conformationally defined adrenergic agents. 4. 1-(aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom.
abstract: The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000138:chemical synthesis*; D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D004285:Dogs; D005260:Female; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D013058:Mass Spectrometry; D008744:Methylamines / Q000138:chemical synthesis / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000187:drug effects / Q000378:metabolism*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D000316:Adrenergic alpha-Agonists; D001572:Benzofurans; D007202:Indicators and Reagents; D008744:Methylamines; D011942:Receptors, Adrenergic, alpha