A new series of naphthalene analogs of medetomidine have been prepared and evaluated for their alpha-adrenergic activities. The methylnaphthyl analog 5a showed significant selectivity for alpha 2-adrenoceptors and behaved as a partial alpha 1-agonist in rat aorta preparations. In contrast, the Z-ethylene analog 8c was alpha 1-selective and behaved as a potent alpha 1-antagonist. Two rigid analogs (6 and 7) exhibited large differences in binding affinities at alpha 1-VS alpha 2-receptors, indicating that the conformational flexibility of 5a is important for the fulfillment of the alpha-adrenergic activities. Molecular modeling studies began with conformational analysis of classical phenethylamines and medetomidine analogs. Superimposition of medetomidine conformations with those of phenethylamines provided a tentative explanation for the alpha 2-adrenergic activity of the new imidazoles. A common binding mode for phenethylamines and imidazoles with alpha 2-adrenoceptors is proposed. Knowledge of the biological properties of the 4-substituted imidazoles, integrated with the information derived from computer-assisted molecular modeling, has provided new insights for the structural and conformational requirements of this class as new adrenergic drugs.

Seven analogues of medetomidine and naphazoline were synthesized and evaluated for their alpha 1 (aorta) and alpha 2 (platelet) activities. The analogues were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either the 1- or 2-naphthalene ring system. In general the 1-naphthalene analogues were the most potent inhibitors of epinephrine-induced platelet aggregation. Of considerable interest was the fact that the 1-naphthalene analogues (2, 5-7) were partial agonists while the 2-naphthalene analogues (3, 8, 9) were antagonists in an alpha 1-adrenergic system (aorta). Thus, appropriately substituted naphthalene analogues of medetomidine and naphthazoline provide a spectrum of alpha 1-agonist, alpha 1-antagonist, and alpha 2-antagonist activity.

Synthesis of new bis(1-methylpyridinium) compounds containing a 1,4-diacetylbenzene linkage between the pyridinium moieties from commercially available 2-, 3-, and 4-picoline precursors was accomplished via metallation, reaction of the picolyllithium with 1,4-dicyanobenzene, and subsequent quaternization of the resulting bispyridyl compounds. Acetylcholinesterase inhibitory activity was determined colorimetrically with purified electric eel enzyme. Examination of structure-activity relationships indicated that the 3-substituted pyridinium compound is the most potent isomer, followed by the 2-substituted isomer, and that the 4-substituted analogue is the least active.

Rats were injected SC with a dose of 10 mg/kg (as base) of 3,4-methylenedioxyamphetamine (MDA), or 3,4-methylenedioxymethamphetamine (MDMA), 4-hydroxy-3-methoxyamphetamine, α-methyldopamine and α-methylnorepinephrine, metabolites of MDA, and α-methylepinephrine, a putative metabolite of MDMA, twice daily for either 5 or 7 consecutive doses. The rats were killed 24 h after the last injection and monoamines in discrete brain regions were assayed. MDA, MDMA, 4-hydroxy-3-methoxyamphetamine and α-methyldopamine, but not α-methylepinephrine, decreased the concentration of serotonin (5-HT) in the frontal cortex. MDA and MDMA, but not 4-hydroxy-3-methoxyamphetamine, α-methyldopamine and α-methylepinephrine, also decreased the concentration of 5-hydroxyindoleacetic acid (5-HIAA) in the frontal cortexes. In stimulatory studies, MDA and MDMA, but not their metabolites except α-methylepinephrine, which increased activity at 15 and 30 min, increased locomotor activity from 15 to 180 min following the drug administration.