Alvameline
Alvameline (Lu 25-109) is a M receptor agonist and M/M receptor antagonist that was under investigation for the treatment of Alzheimer's disease, but produced poor results in clinical trials and was subsequently discontinued. Synthesis. Though the exact cause of Alzheimer’s disease is still unclear, evidence points to the utility of increasing acetylcholine (ACh) levels for treating that condition. Most approaches are aimed at devising inhibitors of cholinesterase, the enzyme that destroys ACh. A quite different tack involves developing compounds that have cholinergic activity in their own right. The tetrazole alvameline (8), for example, was developed  as a bioisostere of the muscarinic cholinergic compound arecoline. The design devolves on the fact that the proton on a free tetrazole shows a (p"K") comparable to that of a carboxylic acid. Fully substituted tetrazoles as in (), may thus in some ways may be viewed as surrogate esters. Alkylation of nicotinonitrile (accessible from nicotinamide)) (1) with methyl iodide affords the "N"-methylpyridinium salt (2). Treatment of this intermediate with sodium borohydride reduces it to 3-cyano-"N"-methyl-1,2,5,6-tetrahydropyridine (3) in which the position of the double bond mimics that in arecoline. Reaction of (3) with ethyl chloroformate results in "N"-demethylation and consequent  formation of the corresponding carbamate. The nitrile group is then transformed to a tetrazole by reaction with sodium azide in the presence of aluminum chloride, one of the standard procedures for building that ring. The surrogate acid is then alkylated with ethyl iodide to afford (6). Treatment with acid then removes the carbamate on the ring nitrogen (7) and the methyl group on the piperidine ring restored using formaldehyde and formic acid under standard Eschweiler–Clarke conditions, yielding the muscarinic agonist alvameline (8).