Synthesis and pharmacology of 1-alkyl-3-(1-naphthoyl)indoles: Steric and electronic effects of 4- and 8-halogenated naphthoyl substituents

Abstract

To develop SAR at both the cannabinoid CB1 and CB2 receptors for 3-(1-naphthoyl)indoles bearing moderately electron withdrawing substituents at C-4 of the naphthoyl moiety, 1-propyl and 1-pentyl-3-(4-fluoro, chloro, bromo and iodo-1-naphthoyl) derivatives were prepared. To study the steric and electronic effects of substituents at the 8-position of the naphthoyl group, the 3-(4-chloro, bromo and iodo-1-naphthoyl)indoles were also synthesized. The affinities of both groups of compounds for the CB1 and CB2 receptors were determined and several of them were evaluated in vivo in the mouse. The effects of these substituents on receptor affinities and in vivo activity are discussed and structure-activity relationships are presented. Although many of these compounds are selective for the CB2 receptor, only three JWH-423, 1-propyl-3-(4-iodo-1-naphthoyl)indole, JWH-422, 2-methyl-1-propyl-3-(4-iodo-1-naphthoyl)indole, the 2-methyl analog of JWH-423 and JWH-417, 1-pentyl-3-(8-iodo-1-naphthoyl)indole, possess the desirable combination of low CB1 affinity and good CB2 affinity.

Moving around the molecule: Relationship between chemical structure and in vivo activity of synthetic cannabinoids

“…Pravadoline, and a similar analog without 2-methylation, do not bind to the CB 1 receptor and are not active in the tetrad tests (Compton, et al, 1992). This pattern of results suggests that steric influences are as important for aminoalkylindoles and 1-pentyl-3-phenylacetylindoles as they are for the halogenated 1-alkyl-3-(1-naphthoyl)indoles (Wiley, et al, 2012b). …”

“…The effects of moderately electron withdrawing halogen substituents (Br, Cl, F, and I) at C-4 or C-8 (see chemical structure at the top of Table 3) on CB 1 and CB 2 receptor affinities and in vivo pharmacology were examined in a series of 1-alkyl-3-(1-naphthoyl)indoles (Wiley, et al, 2012b). In addition, two electroneutral structural features (the length of the N-alkyl group and the presence of a methyl at the 2-indole position) were manipulated in this series.…”

“…Less variability occurred across halogen groups. The authors hypothesized that steric interference with aromatic stacking was a probable cause of the decreased activity of compounds with C-8 substituents (Wiley, et al, 2012b). …”

“…In addition, new in vivo data are presented for structurally related indoles and pyrroles. These unpublished data were collected in the same lab and under the same experimental parameters used for the previously published data (Wiley, et al, 2012a; Wiley, et al, 2012b; Wiley, et al, 1998). Animals used in these experiments were cared for in accordance with the guidelines of the Institutional Animal Care and Use Committee of the Virginia Commonwealth University (Richmond, Virginia) and the ‘Guide For The Care And Use Of Animals’ (National Research Council, 1996).…”

Discovery of High-Affinity Cannabinoid Receptors Ligands through a 3D-QSAR Ushered by Scaffold-Hopping Analysis

“…The models were created using a set of 312 CB 1 receptor ligands, and 187 CB 2 receptor ligands. Details of all the compounds having experimentally determined K i values were retrieved from the literature (i.e., anandamide analogues, benzoyl/alkoyl-indoles, cyclohexylphenols, dibenzopyrans, indazole derivatives, indazole-carboxylates, indazole-carboxamides, indole-carboxylates, indole-carboxamides, naphthoyl-benzimidazoles, naphthoyl-indazoles, naphthoyl-indoles, naphthoyl-naphthalenes, naphthoyl-pyrroles and phenylacetyl-indoles) [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. Figure 1 details the structures of some example of CB 1 and CB 2 ligands.…”