Potential Antisecretory Antidiarrheals. 2. α2-Adrenergic 2-imidazolines

Article abstract of DOI:10.1021/jm00164a024

Lofexidine, an α₂-agonist, has central hypotensive activity and peripheral intestinal antisecretory activity.Analogues were synthetsized with increased polarity in an attempt to prevent penetration of the blood-brain barrier.The compounds were evaluated in the cholera toxin treated ligated jejunum of the rat and in the Ussing chamber with a rabbit ileum preparation.Active compounds were determined to be α₂-adrenergic agonists by yohimbine reversals of their Ussing chamber activities.The 2,6-dimethyl derivative of lofexidine, 4a, was as active as lofexidine invivo, but derivatives with 2,6-substituents larger than ethyl were inactive. (Aryloxy)alkyl derivatives which have an imidazoline and a methyl or larger group as part of the alkyl exhibited the best antisecretory activity.Compounds with substituents in the para position of the phenyl ring were generally inactive. 3-Amino-2,6-dimethyl derivative 21 was twice as active as 4a.A 2-methyl substituent is required in the 3-amino series to retain good activity. 2-methyl derivative 12a had activity comparable to that of 4a, while 6-methyl derivative 12f was inactive.Substituents on the 3-amino group did not affect the activity, but substituting a hydroxyl for the amino group produced an inactive compounds.Replacing the phenyl moiety with a 4-indole resulted in retention of activity, but other heterocycles were inactive.Compound 12a was resolved and d isomer 32 was five times more potent than l isomer 33.The more active compounds in the rat cholera toxin assey (RCTA), when evaluated in the dog, exhibited antisecretory activity but also exhibited centaral nervous system (CNS) effects, sedation and ataxia, at 10 mg/kg, and in spontaneouslyhypertensive rats at 50 mg/kg.A measure of polarity, log P, was calculated for the (aryloxy)alkyl groups.Regression analysis showed no correlation of antisecretory ED₅₀ to the calculated log P.The active compounds did not show a separation of the central CNS effects from the peripheral antisecretory activity by increasing the polarity.