Synthesis and alpha-adrenergic activities of 2-and 4-substituted imidazoline and imidazole analogs of -and B-naphthalene

Seven analogs of medetomidine and naphazoline were synthesized and evaluated for their alpha 1- [aorta] and alpha 2- [platelet] activities. The analogs were composed of 2- and 4-substituted imidazoles and imidazolines attached through a methylene bridge to either an alpha- or beta-naphthalene ring system. In general, the alpha-naphthalene analogs were found to be the most potent inhibitors of platelet aggregation. The fact that the alpha-naphthalene analogs [2, 5, 6, and 7] were partial agonists, while the beta-naphthalene analogs [3, 8, 9] were antagonists in alpha 1-adrenergic system [aorta] was reported. Thus, appropriately substituted naphthalene analogs of medetomidine and naphazoline provided a broad spectrum of alpha 1-[agonist and antagonist] activity and alpha 2-antagonist activities

Medetomidine analogs as alpha-adrenergic agonists

There are two major classes of drugs that interact with adrenergic receptors. Recently, it has been reported that medetomidine is a new 4-substituted imidazole analog possessing selective and potent alpha 2-adrenergic properties. It was shown that it reduces blood pressure, heart rate and saliva secretion. At the present time, its sedative and hypotensive effects to be manifest in the same dose range. A program was initiated to see if it is possible to separate these activities with analogs of medetomidine. The initial studies were directed at procedures for the conversion of the imidazoline, a common structure of alpha-adrenergic drugs, to the corresponding imidazoles. It was found that 2-substituted and 2,4-disubstituted imidazolines can easily be converted into imidazoles using 10% Pd/C in refluxing toluene while in some instances there are some difficulties with the conversion of 4-substituted imidazolines to the imidazoles. The synthesis of 1- or 2-[2- or 4-imidazolylmethyl] naphthalene analogs of medetomidine was also described