BACKGROUND AND PURPOSE: The aim of this study was to develop potent and long-acting antagonists of muscarinic ACh receptors. The 4-hexyloxy and 4-butyloxy derivatives of 1-[2-(4-oxidobenzoyloxy)ethyl]-1,2,3,6-tetrahydropyridin-1-ium were synthesized and tested for biological activity. Antagonists with long-residence time at receptors are therapeutic targets for the treatment of several neurological and psychiatric human diseases. Their long-acting effects allow for reduced daily doses and adverse effects. EXPERIMENTAL APPROACH: The binding and antagonism of functional responses to the agonist carbachol mediated by 4-hexyloxy compounds were investigated in CHO cells expressing individual subtypes of muscarinic receptors and compared with 4-butyloxy analogues. KEY RESULTS: The 4-hexyloxy derivatives were found to bind muscarinic receptors with micromolar affinity and antagonized the functional response to carbachol with a potency ranging from 30 nM at M1 to 4 μM at M3 receptors. Under washing conditions to reverse antagonism, the half-life of their antagonistic action ranged from 1.7 h at M2 to 5 h at M5 receptors. CONCLUSIONS AND IMPLICATIONS: The 4-hexyloxy derivatives were found to be potent long-acting M1 -preferring antagonists. In view of current literature, M1 -selective antagonists may have therapeutic potential for striatal cholinergic dystonia, delaying epileptic seizure after organophosphate intoxication or relieving depression. These compounds may also serve as a tool for research into cognitive deficits.

Department of Neurochemistry Institute of Physiology Czech Academy of Sciences Prague Czech Republic

Department of Physical Sciences Barry University Miami Shores FL USA

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