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Bis(ammonio)alkane compounds carrying lateral phthalimidopropyl substituents on the nitrogen atoms belong to the archetypal muscarinic allosteric agents. Herein, a series of symmetrical and nonsymmetrical compounds was synthesized in which the phthalimide residues were replaced by differently substituted imide moieties. The allosteric action was measured in porcine heart muscarinic M(2) receptors using [(3)H]N-methylscopolamine (NMS) as a ligand for the orthosteric receptor site in equilibrium binding and dissociation experiments. 1,8-Naphthalimido residues conferred an up to 100-fold gain in affinity leading into the low nanomolar range, while the inhibition of NMS binding was maintained. Additional propyl chain methylation was accompanied by an allosteric elevation of orthosteric ligand binding. In general, the gain in allosteric activity achieved by ring variation plus propyl chain methylation on one side of the molecule could not be augmented by symmetrical variations. The elevation of the ligand binding can be explained by different quantitative structure-activity relationships for the affinities to the free and the orthoster-liganded receptor.

Although four different subtypes of the muscarinic acetylcholine (ACh) receptor with functional correlates are known to exist (function for M5 is still unclear), all muscarinic agonists and antagonists in clinical practice only show very weak selectivity. Therefore, intensive investigations are in progress to develop subtype selective ligands. This review describes the first M1 agonists and antagonists of the presynaptic M2 receptor, which can be used in the treatment of Alzheimer's disease (AD), and M3 antagonists, which will be useful in the treatment of urinary urge incontinence. In addition, muscarinic agonists were found to exhibit analgesic effects and M4 antagonists may be useful in the treatment of movement disorders. However, the latter two pharmacological findings will need more research work to become established in clinical trials.

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