1, l-Dimethyl-4-phenylpiperazinium

Acetylgramine. This substance is active (IV. in mice) at doses of 5 mg per kg and less, making it quite potent. It potentiates response to DMPP (l,l-Dimethyl-4-phenylpiperazinium iodide) and blocks response to acetylcholine and adrenalin. Reflux a mixture of 15 g of 5-aeetylindole or analog (in equimolar amount), 7.55 g of 37% aqueous formaldehyde, 17 g of 25% aqueous di-methylamine, 25 ml of acetic acid, and 250 ml of methanol for 3 hours. Concentrate in vacuo to 20% of original volume, treat with 100 ml of water, wash with chloroform, chill in freezer, and make basic with 20% NaOH. Filter off the crystalline precipitate and wash with cold (near freezing) water to get a little over 17 g of the title product. Recrystallize from benzene to purify. It is unknown to me if this is active orally. 

In 1993, as ABT-418 progressed through the course of early clinical trials, the pressing mission of the medicinal chemistry group was to prepare potential backup compounds. A matter of some debate was whether another isoxazole-like compound should suffice as a backup, or whether an entirely different series needed to be identified. A number of known nAChR ligands with diverse structures, such as anatoxin-a (5), l,l-dimethyl-4-phenylpiperazinium (6), and iV-methylcarbamyl choline (7), could potentially serve as lead compounds, and indeed many of these, as well as numerous isoxazole variants, were explored to at least some degree. 

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