.alpha.2-Adrenergic agonists/antagonists: the synthesis and structure-activity relationships of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines

Abstract

The synthesis and alpha 2-adrenergic activity of a series of indolin-2-yl and tetrahydroquinolin-2-yl imidazolines are described. The indolin-2-yl imidazoline 4b was found to possess potent alpha 2-adrenergic agonist and antagonist activity. The modification of the substituents on the indoline ring of 4b has led to the separation of these activities. Substitution on the aromatic ring of 4b with halogen or increasing the size of the N-alkyl substituent of 4b gave alpha 2-adrenergic antagonists without agonist activity. The N-allylindoline 4d is more potent than idazoxan in vitro and is equipotent in vivo, but is less receptor selective (alpha 2 vs. alpha 1) than idazoxan. The cis-1,3-dimethylindolin-2-yl imidazoline 6a is an alpha 2-adrenergic agonist equal in potency to clonidine in vitro, while the trans-1,3-dimethylindolin-2-yl imidazoline 6b is a moderately potent alpha 2-adrenergic antagonist.

Third‐generation antidepressants

“…4). [88][89][90][91][92][93] Due to their close structural relationship with known a-adrenoceptor agonists several series do show partial agonistic character and interesting combinations have been obtained. Idazoxan itself, being a partial agonist in some test models, has and continues to be an interesting tool for pharmacological research, contributing to our understanding of a,-adrenoceptor subtypes and imidazoline recognition sites (see also below).94 Meanwhile idazoxan has been under clinical evaluation as an antidepressant for a considerable time now, but a definite proof of efficacy in placebo-controlled trials seems not to have been obtained as yet.…”

Direct Aminoalkylation of Arenes, Heteroarenes, and Alkenes via Ni-Catalyzed Negishi Cross-Coupling Reactions

“…23 Reduction of the quinoline ring with NaBH 4 in the presence of NiCl 2 (18 mol %) led to piperidine 15 in 87% yield, 24 which was submitted to an aminoalkylation using formaldehyde and Na-(BH 3 )CN, 25 yielding the corresponding N-methyl-piperidine 16 in quantitative yields. A chlorination with thionyl chloride in CH 2 Cl 2 26 gave the amine 17 in 83% yield.…”

Design, synthesis and preliminary pharmacological evaluation of rigid analogues of the nicotinic agonist 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP)

“…Finally, treatment of 2a with benzyl chloroformate gave 7, which was then reduced with LiAlH 4 affording 2b with good yield. Compounds 2a and 2b were successfully reduced with NaBH 3 CN in acetic acid 29 obtaining the corresponding 1,2,3,4,10,10a-hexahydropyrazino[1,2-a]indoles 4a 30 and 4b. Methiodides 2c and 4c were then obtained by treatment with MeI in ether.…”