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Potential antisecretory antidiarrheals. 2. Alpha 2-adrenergic 2-[(aryloxy)alkyl]imidazolines
A E Moormann1, B S Pitzele, P H Jones
1Preclinical Research, G. D. Searle and Company, Skokie, Illinois 60077.
Journal of Medicinal Chemistry
|February 1, 1990
Summary
Researchers synthesized lofexidine analogues to enhance intestinal antisecretory activity while minimizing central nervous system (CNS) effects. The study identified potent derivatives but found increased polarity did not separate peripheral from central activity.
Area of Science:
- Medicinal Chemistry
- Pharmacology
- Gastroenterology
Background:
- Lofexidine, an alpha 2-agonist, possesses hypotensive and intestinal antisecretory properties.
- Existing analogues aimed to reduce central nervous system (CNS) penetration by increasing polarity.
- Understanding structure-activity relationships is crucial for developing targeted antisecretory agents.
Purpose of the Study:
- To synthesize and evaluate novel lofexidine analogues for enhanced peripheral intestinal antisecretory activity.
- To investigate the impact of structural modifications, including polarity, on pharmacological effects.
- To determine if central nervous system (CNS) effects can be dissociated from peripheral antisecretory activity.
Main Methods:
- Synthesis of lofexidine analogues with varied substituents and polarity.
- In vivo evaluation using the rat cholera toxin-induced diarrhea model (RCTA).
- In vitro assessment using Ussing chamber preparations of rabbit ileum.
- Pharmacological characterization including yohimbine reversal and assessment of CNS side effects in vivo.
Main Results:
- Several analogues demonstrated potent antisecretory activity comparable to or exceeding lofexidine.
- Specific structural features, such as 2,6-dimethyl substitution and (aryloxy)alkyl moieties, were critical for activity.
- Increased polarity did not correlate with reduced CNS effects (sedation, ataxia) or enhanced antisecretory potency.
- The D-isomer of a resolved analogue showed significantly higher potency than the L-isomer.
Conclusions:
- Structural modifications can yield potent intestinal antisecretory agents based on the lofexidine scaffold.
- Achieving selective peripheral antisecretory activity without CNS side effects remains a challenge.
- Further research is needed to dissociate central and peripheral activities of alpha 2-adrenergic agonists.