Design and synthesis of a diverse morpholine template library.

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.

Structure-activity relationships of indole- and pyrrole-derived cannabinoids.

Early molecular modeling studies with Delta9-tetrahydrocannabinol (Delta9-THC) reported that three discrete regions which interact with brain cannabinoid (CB1) receptors corresponded to the C-9 position of the cyclohexene ring, the phenolic hydroxyl and the carbon side chain at the C3 position. Although the location of these attachment points for aminoalkylindoles is less clear, the naphthalene ring, the carbonyl group and the morpholinoethyl group have been suggested as probable sites. In this study, a series of indole- and pyrrole-derived cannabinoids was developed, in which the morpholinoethyl group was replaced with another cyclic structure or with a carbon chain that more directly corresponded to the side chain of Delta9-THC and were tested for CB1 binding affinity and in a battery of in vivo tests, including hypomobility, antinociception, hypothermia and catalepsy in mice and discriminative stimulus effects in rats.

Evidence for the presence of CB2-like cannabinoid receptors on peripheral nerve terminals.

We have investigated whether there are cannabinoid CB2 receptors that can mediate cannabinoid-induced inhibition of electrically evoked contractions in the mouse vas deferens or guinea-pig myenteric plexus-longitudinal muscle preparation. Our results showed that mouse vas deferens and guinea-pig whole gut contain cannabinoid CB1 and CB2-like mRNA whereas the myenteric plexus preparation seemed to contain only cannabinoid CB1 mRNA. JWH-015 (1-propyl-2-methyl-3-( -naphthoyl)indole) and JWH-051 (1-deoxy-11-hydroxy-delta8-tetrahydrocannabinol-dimethylheptyl+ ++), which have higher affinities for CB2 than CB1 cannabinoid binding sites, inhibited electrically evoked contractions of both tissues in a concentration related manner.

Pharmacological characterization of three novel cannabinoid receptor agonists in the mouse isolated vas deferens.

The novel compounds, 1-pentyl-2-methyl-3-(1-naphthoyl)indole, 1-pentyl-3-(1-naphthoyl)pyrrole and 1-heptyl-3-(1-naphthoy)indole, produced a dose-related inhibition of electrically evoked contractions of the mouse vas deferens, with IC50 values of 2.56 nM, 3.38 nM and 639 nM respectively.

Variation of the alkyl side chain in delta 8-THC.

The synthesis of (2'RS)-2'-methyl-, (3'RS)-, (3'S)-3'-methyl-, and 4'-methyl-delta 8-THC has been carried out, and the pharmacology of all four compounds has been investigated. All four compounds showed typical cannabinoid activity both in vitro and in vivo. The 2'-methyl compound is somewhat more active than delta 8-THC, while the 4'-methyl isomer is less active.