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

Abstract

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.

Medetomidine Analogs as α2-Adrenergic Ligands. 2. Design, Synthesis, and Biological Activity of Conformationally Restricted Naphthalene Derivatives of Medetomidine

“…7,27 Results are summarized in Table 2. On rat aorta, the R 1 -adrenoceptor responses were expressed as a percentage of the maximum contraction to 1 µM of phenylephrine.…”

“…IC50 values of drugs were analyzed by computer programs as described previously. 27 X-ray Analysis of 8c. A clear colorless 0.36 × 0.36 × 0.52 mm data crystal of 8c (C16H15N2 + ‚C4H3O4 -), fw ) 350.4) was crystallized from CHCl3/hexane.…”

Resolution and adrenergic activities of the optical isomers of 4‐[1‐(1‐Naphthyl)ethyl]‐1H‐imidazole

“…16 In the separation of the 4-[l-( 1-naphthyl)ethyl]-1H-imidazole enantiomers, it was possible to use either a fractional crystallization or chiral highperformance liquid chromatography (HPLC). Fractional crystallization was chosen because of the large quantities of each enantiomer needed for in vivo testing.…”

Azi-medetomidine: Synthesis and Characterization of a Novel α2 Adrenergic Photoaffinity Ligand

“…The decreased potency of azi-medetomidine at the adrenergic α 2A -R in comparison to its parent compound is not unexpected given substitutions on the aromatic ring of imidazoline/imidazole α 2 agonists significantly alter adrenergic receptor affinity. 23,24 As optical orientation of the chiral methyl group significantly affects potency of medetomidine derivatives, we hypothesize that the dextrorotary enantiomer of azimedetomidine is the active enantiomer at the adrenergic α 2A -R, though we were unable to optically purify sufficient compound to test this theory. Though less than that of its parent compound, the measured potency of azi-medetomidine is nevertheless greater than that of the commonly used α 2 adrenergic agonist, xylazine, 18 and thus a reasonable substrate for investigation of α 2 adrenergic receptor binding and hypnosis.…”