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 valuable research tool 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 toxic/malodorous. We redesigned the synthetic 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. Our results show that L-822,429 potently inhibited stress-induced reinstatement of alcohol seeking in rats and that this effect was behaviorally specific. These results suggest that NK-1 antagonism as a mechanism to suppress stress-induced alcohol relapse in humans.
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