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Efficient and general procedures have been developed for the solution-phase preparation of substituted morpholine derivatives, and a library has been produced around generic structure 1. This library was designed with proprietary modeling software for use as a general screening library. The 30 R1 reagents were phenols, and the 275 R2 reagents were taken from five different reagent classes, giving a variety of product classes in the final library of 8250 potential products. All of the library members were generated from a common intermediate, mesylate (5), which was synthesized efficiently, in bulk, in three steps from N-benzylethanolamine (2). High-throughput chemistry using robotics was carried out to produce the 7907 library members, which were individually characterized by reversed-phase LC/MS analysis.

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As a result of the recognition of a cannabinoid receptor, the isolation of the first endogenous cannabinoid and, more recently, the significant discovery of a cannabinoid antagonist, there has been a resurgence of interest in the medicinal chemistry of cannabinoids. This has included inter alia investigations into the effects of side chain substitution and overall molecular geometry on the biological activity of traditional cannabi­ noids, which are partially reduced dibenzopyrans, as well as the design and synthesis of a variety of non-traditional cannabinoids. These compounds include indole and pyrrole derivatives, which are agonists, a diarylpyrazole, which is the first cannabinoid antagonist, and various amides of arachidonic acid. The latter compounds are patterned on anandamide (arachidonic acid ethanolamide), the first endogenous cannabinoid isolated from mammalian brain tissue. Modeling studies of the cannabinoid receptor are beginning to provide some insight into the interaction of various agonists with the receptor. This article will review recent developments in the medicinal chemistry of cannabinoids with an emphasis on work reported since 1992.