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HCN4 channels are considered to be a promising target for cardiac pathologies, epilepsy, and multiple sclerosis. However, there are no subtype-selective HCN channel blockers available, and only a few compounds are reported to display subtype preferences, one of which is EC18 (cis-1). Herein, we report the optimized synthetic route for the preparation of EC18 and its evaluation in three different pharmacological models, allowing us to assess its activity on cardiac function, thalamocortical neurons, and immune cells., (© 2023 Deutsche Pharmazeutische Gesellschaft.)

The binding profile on sigma receptor subtypes of a family of tropane derivatives, previously studied as analgesic and nootropic drugs, is reported. The results show that the sigma receptors are not involved in the enhancement of acetylcholine release and of the consequent analgesic activity of this class of drugs. Structure-affinity relationships for sigma receptor subtypes are discussed. They lead to the identification of a few useful leads for further development of potent sigma ligands within the series.

Molecular modification of the potent and selective muscarinic antagonist 2-ethylthio-2,2-diphenylacetic acid N,N-diethylaminoethyl ester was performed in order to identify M2 selective antagonists able to cross the blood brain barrier and potentially useful in the treatment of Alzheimer's disease. Modifications included substitution or hydrogenation of one of the phenyl rings as well as their incorporation in a tricyclic system. In general the changes introduced were detrimental for both affinity and selectivity. Only a modest M2 selectivity is present in some compounds that, on the other hand, carry a quaternary ammonium group which precludes their penetration into the brain.

A series of semirigid analogs of compounds 1 and 2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg 22 is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5-HT4 antagonist SDZ 205557, the possible role of this receptor is discussed.