Pharmacological Characterization of the Novel ACh Releaser α‐tropanyl 2‐(4‐bromophenyl)propionate (PG‐9)

Ghelardini et al. (27) reported that atropine at very low doses induces central antinociception in rodents through an enhancement of cholinergic transmission. Soon after, it was discovered that the R-(+)-enantiomer of atropine, R-(+)-hyoscyamine, was responsible for the antinociceptive activity of the racemate, while the S-(–)-enantiomer, S-(–)-hyoscyamine, was devoid of any antinociceptive action (29). R-(+)-hyoscyamine, in the same range of analgesic doses, was also able to prevent amnesia induced by antimuscarinic drugs (35). It is interesting to note that this antinociceptive activity, different from that produced by direct muscarinic agonists and cholinesterase inhibitors, was not accompanied by typical cholinergic symptoms (e.g., tremors, sialorrhea, diarrhea, rhinorrhea, lacrimation). An investigation of the antinociceptive and antiamnesic effect of atropine has demonstrated, using microdialysis techniques, that R-(+)-hyoscyamine, at cholinomimetic doses, produced an increase in acetylcholine (ACh) release from the rat cerebral cortex in vivo, indicating that it acts via a presynaptic mechanism (35). On this basis, a synthetic program to modify the chemical structure of atropine was started, which aimed to develop cholinergic amplifiers endowed with more intensive antinociceptive and antiamnesic activities than atropine but, like atropine, lacking cholinergic side effects. These compounds would, therefore, be potentially useful as analgesics and or in pathological conditions characterized by cholinergic deficits (e.g., Alzheimer’s