Synthesis and structure–activity relationships of a series of pyrrole cannabinoid receptor agonists

Abstract

Abstract-We designed and synthesized a series of pyrrole derivatives with the aim of investigating the structure-activity relationship (SAR) for the binding of non-classical agonists to CB 1 and CB 2 cannabinoid receptors. Superposition of two pyrrole-containing cannabinoid agonists, JWH-007 and JWH-161, allowed us to identify positions 1, 3 and 4 of the pyrrole nucleus as amenable to additional investigation. We prepared the 1-alkyl-2,5-dimethyl-3,4-substituted pyrroles 10a-e, 11a-d, 17, 21, 25 and the tetrahydroindole 15, and evaluated their ability to bind to and activate cannabinoid receptors. Noteworthy in this set of compounds are the 4-bromopyrrole 11a, which has an affinity for CB 1 and CB 2 receptors comparable to that of well-characterized heterocyclic cannabimimetics such as Win-55,212-2; the amide 25, which, although possessing a moderate affinity for cannabinoid receptors, demonstrates that the 3-naphthoyl group, commonly present in indole and pyrrole cannabimimetics, can be substituted by alternative moieties; and compounds 10d, 11d, showing CB 1 partial agonist properties. #

Pharmacological Profile of the Selective FAAH Inhibitor KDS-4103 (URB597)

“…1) (1,27,37,47,48). The index member of the latter group of compounds, the compound URB597 (KDS-4103) ( Fig.…”

Recent developments in cannabinoid ligands

“…Several new ligands are shown in Table 8 (Tarzia et al, 2003). The concomitant presence of methyl substituents at both a-positions of the pyrrole (125) results in a moderate decrease in affinity for the CB 1 H]WIN55212-2 in at least three independent experiments run in duplicate and expressed as the mean of three values with standard error of mean.…”

“…Alterations to the 3-aroyl substituent provide compounds with dramatically attenuated potency, speaking strongly for the distal naphthyl ring interacting directly with the ligand binding pocket (Tarzia et al, 2003). The use of a benzoyl substituent gives compounds with no appreciable affinity (132-134).…”

The endogenous cannabinoid system and the treatment of marijuana dependence

“…The search for small-molecule inhibitors of intracellular FAAH activity has led to the emergence of several potent and selective agents, which include substituted sulfonyl fluorides (Gifford et al, 1999), alpha-keto-oxazolopyridines (Boger et al, 2001) and carbamic acid esters Tarzia et al, 2003). The latter were identified during structureactivity relationship studies aimed at determining whether esters of carbamic acid such as the insecticide carbaryl inhibit FAAH activity.…”