Recent work has suggested that antagonism of neurokinin-1 (NK-1, Substance P) may be useful in the treatment and prevention of alcohol abuse. The chiral NK-1 receptor antagonist L-822,429 is a potentially needed for collaborative work with Markus Helig (NIAAA) and Yavin Shaham (NIDA) in this area. The only published synthetic sequence is a difficult and low yielding patent process that utilizes starting materials that are either prohibitively expensive and/or prohibitively malodorous. We redesigned the route incorporating mostly novel methodology that eliminated the expensive and toxic, malodorous reagents and improved the overall yield from 0.9% to 12% (13 fold increase in yield). Even then, the synthesis required beginning with hundreds of grams of starting materials, and 14 steps overall and required optical resolution of an intermediate. The cyclopropoxy group present in L-822,429 is a significant complication in the synthesis since introduction of the cyclopropoxy function requires indirect methods and adds 3 steps as direct phenolic alkylation with cyclopropyl bromide does not work. We synthesized about 40 grams of L-822,429 that is presently being studied. We also tested the hypothesis that sigma receptors modulate ethanol reinforcement and contribute to excessive ethanol intake. We utilized the potent, selective sigma-1 receptor antagonist BD-1063 developed earlier in our laboratory in a number of rat models of alcohol self-administration. Our results also suggest that sigma receptor may contribute to innate or ethanol-induced increases in susceptibility to self-administer high ethanol levels, identifying a potential neuroadaptive mechanism contributing to excessive drinking and a therapeutic target for alcohol abuse and dependence.
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