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.The synthesis and pharmacology of 1-alkyl-3-(4-halo-1-naphthoyl)indoles and 1-alkyl-3-(8-halo-1-naphthoyl)indoles (R = C3H7 and C5H11, R′ = H and CH3) is described. Three of these compounds have useful selectivity for the CB2 receptor.

Three 1-methoxy analogs of CP-47,497 (7, 8, and 19) have been synthesized and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. Although these compounds exhibit selectivity for the CB2 receptor none have significant affinity for either receptor. Modeling and receptor docking studies were carried out, which provide a rationalization for the weak affinities of these compounds for either receptor.The synthesis and pharmacology of three 1-methoxy analogs of CP-47,497 (n = 4 and 5) are described. The CB1 and CB2 receptor affinities of these compounds are reported. Molecular modeling and receptor docking studies are presented.

Δ8-Tetrahydrocannabinol (26), 3-(1′,1′-dimethylbutyl)- (12), 3-(1′,1′-dimethylpentyl)- (13), 3-(1′,1′-dimethylhexyl)- (14) and 3-(1′,1′-dimethylheptyl)-Δ8-tetrahydrocannabinol (15) have been converted into the corresponding 1-bromo-1-deoxy-Δ8-tetrahydrocannabinols (25, 8–11). This was accomplished using a protocol developed in our laboratory in which the trifluoromethanesulfonate of a phenol undergoes palladium mediated coupling with pinacolborane. Reaction of this dioxaborolane with aqueous-methanolic copper(II) bromide provides the aryl bromide. The affinities of these bromo cannabinoids for the cannabinoid CB1 and CB2 receptors were determined. All of these compounds showed selectivity for the CB2 receptor and one of them, 1-bromo-1-deoxy-3-(1′,1′-dimethylhexyl)-Δ8-tetrahydrocannabinol (10), exhibits 52-fold selectivity for this receptor with good (28 nM) affinity.The synthesis and pharmacology of a series of 1-bromo-1-deoxy-3-(1′,1′-dimethylalkyl)-Δ8-THCs is described. One of these compounds (R = dimethylhexyl) is 52-fold selective for the CB2 receptor with good (28 nM) affinity for this receptor.

A series of 1-deoxy analogs of CP-47,497 (8 and 13, n = 0–7) and 1-deoxy analogs of CP-55,940 (9, n = 0–7) have been synthesized and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. Although the majority of these compounds exhibit selectivity for the CB2 receptor, none have greater than modest affinity for either receptor. The interactions of these 1-deoxy nontraditional cannabinoids with the CB2 receptor are discussed.The synthesis and pharmacology of a series of 1-deoxy analogs of CP-47,497 (R = H, n = 0–7), both epimeric alcohols and 1-deoxy analogs of CP-55,940 (R = C3H6OH, n = 0–7), β-hydroxy only, is described. The CB1 and CB2 receptor affinities of these compounds are reported.

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2′R)- and (2′S)-1-methoxy- and 1-deoxy-3-(2′-methylalkyl)-Δ8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2′R)-1-methoxy-3-(2′-methylbutyl)-Δ8-THC (JWH-359), (2′S)-1-deoxy-3-(2′-methylbutyl)-Δ8-THC (JWH-352), (2′S)-1-deoxy-3-(2′-methylpentyl)-Δ8-THC (JWH-255), and (2′R)-1-deoxy-3-(2′-methylpentyl)-Δ8-THC (JWH-255), have good affinity (Ki = 13–47 nM) for the CB2 receptor and little affinity (Ki = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2′-methylalkyl)-Δ8-THC series, the 2′S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2′R isomers.The enantioselective synthesis and pharmacology of two series of (2′R)- and (2′S)-methyl-Δ8-THC ligands are described. R = H, OCH3; R′ = methyl to n-pentyl.

Fourteen novel CB2 receptor selective cannabinoids were synthesized via initial Lewis acid catalyzed rearrangement of resorcinol precursors to obtain the cannabinoid moiety. These are the 1-methoxy-9-hydroxyhexahydrocannabinols and the 1-deoxy-9-hydroxyhexahydrocannabinols, with 1′,1′-dimethylalkyl side chains of four to seven carbon atoms at C-3 of the cannabinoid nucleus. The cannabinols synthesized and described in this paper all exhibit greater affinity for the CB2 receptor than for the CB1 receptor. Exceptionally high CB2 affinity was observed for 1-deoxy-9β-hydroxy-dimethylhexylhexahydrocannabinol (JWH-361, 9, n = 3) Ki = 2.7 nM and 1-deoxy-9β-hydroxydimethylpentylhexahydrocannabinol (JWH-300, 9, n = 2) Ki = 5.3 nM. In general, the stereochemistry of the 9-hydroxy group is important and the β-orientation enhances both CB2 receptor affinity and selectivity.The synthesis and pharmacology of two series of 11-nor-9-hydroxy-HHCs are described. R = H, OCH3; R′ = n-propyl to n-hexyl.

Two series of 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles were synthesized and their affinities for the cannabinoid CB1 and CB2 receptors were determined. In the 2-phenyl series (5) the N-alkyl group was varied from n-propyl to n-heptyl. A second series of 23 1-pentyl-2-aryl-4-(1-naphthoyl)-pyrroles (6) was also prepared. Several compounds in both series have CB1 receptor affinities in the 6–30 nM range. The high affinities of these pyrrole derivatives relative to JWH-030 (1, R = C5H11) support the hypothesis that these pyrroles interact with the CB1 receptor primarily by aromatic stacking.The synthesis and pharmacology of 28 1-alkyl-2-aryl-4-(1-naphthoyl)pyrroles are described. Several of these compounds have high affinity for both the CB1 and CB2 receptors.

In an effort to improve indole-based CB2 cannabinoid receptor ligands and also to develop SAR for both the CB1 and CB2 receptors, 47 indole derivatives were prepared and their CB1 and CB2 receptor affinities were determined. The indole derivatives include 1-propyl- and 1-pentyl-3-(1-naphthoyl)indoles both with and without a 2-methyl substituent. Naphthoyl substituents include 4- and 7-alkyl groups as well as 2-, 4-, 6-, 7-methoxy and 4-ethoxy groups. The effects of these substituents on receptor affinities are discussed and structure–activity relationships are presented. In the course of this work three new highly selective CB2 receptor agonists were identified, 1-propyl-3-(4-methyl-1-naphthoylindole (JWH-120), 1-propyl-2-methyl-3-(6-methoxy-1-naphthoylindole (JWH-151), and 1-pentyl-3-(2-methoxy-1-naphthoylindole (JWH-267). GTPγS assays indicated that JWH-151 is a full agonist at CB2, while JWH-120 and JWH-267 are partial agonists. Molecular modeling and receptor docking studies were carried out on a set of 3-(4-propyl-1-naphthoyl)indoles, a set of 3-(6-methoxy-1-naphthoyl)indoles and the pair of N-pentyl-3-(2-methoxy-1-naphthoyl)indoles. Docking studies indicated that the CB1 receptor affinities of these compounds were consistent with their aromatic stacking interactions in the aromatic microdomain of the CB1 receptor.The synthesis and pharmacology of 47 1-alkyl-3-(1-naphthoyl)indoles (R = C3H7 and C5H11, R′ = H and CH3) is described. Naphthoyl substituents include 4- and 7-alkyl groups, plus 2, 4, 6, and 7-methoxy groups. Three of these compounds are highly selective CB2 receptor agonists.

A new class of cannabimimetic indoles, with 3-phenylacetyl or substituted 3-phenylacetyl substituents, has been prepared and their affinities for the cannabinoid CB1 and CB2 receptors have been determined. In general those compounds with a 2-substituted phenylacetyl group have good affinity for both receptors. The 4-substituted analogs have little affinity for either receptor, while the 3-substituted compounds are intermediate in their affinities. Two of these compounds, 1-pentyl-3-(2-methylphenylacetyl)indole (JWH-251) and 1-pentyl-3-(3-methoxyphenylacetyl)indole (JWH-302), have 5-fold selectivity for the CB1 receptor with modest affinity for the CB2 receptor. GTPγS determinations indicate that both compounds are highly efficacious agonists at the CB1 receptor and partial agonists at the CB2 receptor.The synthesis and pharmacology of 30 1-pentyl-3-arylacetylindoles (R = H and CH3) are described. Two of these compounds are highly efficacious and selective ligands for the CB1 receptor.

A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9–11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12–14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB1 receptor by hydrogen bonding to the carbonyl group. Indoles 9–11 have significant (Ki=17–23 nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12–14 have little affinity for the CB1 receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17–19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have Ki=26±4 nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB1 receptor.The synthesis and pharmacology of 3-indolyl-1-naphthylmethanes (R=H, CH3, OCH3) and related compounds are described. These compounds have CB1 receptor affinities similar to those of 3-(1-naphthoyl)indoles.

A series of 1′,1′-dimethylalkyl-Δ8-tetrahydrocannabinol analogues with C-3 side chains of 2–12 carbon atoms has been synthesized and their in vitro and in vivo pharmacology has been evaluated. The lowest member of the series, 1′,1′-dimethylethyl-Δ8-THC (8, n=0) has good affinity for the CB1 receptor, but is inactive in vivo. The dimethylpropyl (8, n=1) through dimethyldecyl (8, n=8) all have high affinity for the CB1 receptor and are full agonists in vivo. 1′,1′-Dimethylundecyl-Δ8-THC (8, n=9) has significant affinity for the receptor (Ki=25.8±5.8 nM), but has reduced potency in vivo. The dodecyl analogue (8, n=10) has little affinity for the CB1 receptor and is inactive in vivo. A quantitative structure–activity relationship study of the side chain region of these compounds is consistent with the concept that for optimum affinity and potency the side chain must be of a length which will permit its terminus to loop back in proximity to the phenolic ring of the cannabinoid.The structure–activity relationships for a series of 1′, 1′-dimethylalkyl-Δ8-THCs (n=0–10) are discussed in terms of the conformation of the side chain.

A pyridone analogue (5) of the potent bicyclic cannabinoid CP 47,497 (6) has been synthesized as a model for one conformational isomer of anandamide and to test the hypothesis that an amide carbonyl may serve as a hydrogen bond acceptor in interactions with the CB1 cannabinoid receptor. Pyridone 5 was synthesized from 6-bromo-2-methoxypyridine (10) by palladium catalyzed coupling with 1-pentyne to provide 11. Catalytic hydrogenation of 11 and hydrolysis to pyridone 13 followed by N-alkylation gave 1-propyl-6-pentyl-2-pyridone (15). Bromination of 15 gave dibromide 18, which underwent Heck coupling with cyclohex-2-en-1-one to give enone 19. Catalytic hydrogenation of 19 gave ketone 20 which was reduced using NaBH4 to alcohol 5. Reduction of 20 with K-Selectride gave the axial epimer of 5 (21). Neither alcohol 5 nor 21 have significant affinity for the CB1 receptor (Ki > 970 nM), but both have moderately high affinity for the CB2 receptor (Ki < 60 nM).The synthesis and pharmacology of both hydroxyl epimers of a pyridone analogue of traditional cannabinoids are described. Neither compound has significant affinity for the CB1 receptor, but both have affinity in the 50 nM range for the CB2 receptor.

A pentacyclic hybrid cannabinoid ( and ) has been synthesized, which combines structural elements of traditional cannabinoids and cannabmimetic indoles. Cannabinoid  and  contains a 1-pentylindole structure fused to the 2,3-positions of the partially reduced hydroxydibenzopyran system of THC. The successful approach to  and  employed 9-benzoyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole ( and ) as the starting material. Dehydrogenation to carbazole 18, followed by demethylation and condensation with trans-p-menthadienol gave N-benzoyl hybrid cannabinoid 22, N-alkylation of which afforded target cannabinoid  and . The hybrid cannabinoid had affinity for the CB1 receptor approximately equal to that of Δ8-THC (Ki=19.3±3 nM), and shows comparable potency in vivo.

The synthesis and pharmacology of 15 1-deoxy-Δ8-THC analogues, several of which have high affinity for the CB2 receptor, are described. The deoxy cannabinoids include 1-deoxy-11-hydroxy-Δ8-THC (5), 1-deoxy-Δ8-THC (6), 1-deoxy-3-butyl-Δ8-THC (7), 1-deoxy-3-hexyl-Δ8-THC (8) and a series of 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ8-THC analogues (2, n=0–4, 6, 7, where n=the number of carbon atoms in the side chain−2). Three derivatives ( 17–19) of deoxynabilone (16) were also prepared. The affinities of each compound for the CB1 and CB2 receptors were determined employing previously described procedures. Five of the 3-(1′,1′-dimethylalkyl)-1-deoxy-Δ8-THC analogues (2, n=1–5) have high affinity (Ki=<20 nM) for the CB2 receptor. Four of them (2, n=1–4) also have little affinity for the CB1 receptor (Ki=>295 nM). 3-(1′,1′-Dimethylbutyl)-1-deoxy-Δ8-THC (2, n=2) has very high affinity for the CB2 receptor (Ki=3.4±1.0 nM) and little affinity for the CB1 receptor (Ki=677±132 nM).

The synthesis of the 3-heptyl, and the eleven isomeric 3-methylheptyl-Δ8-tetrahydrocannabinols (3–7, R and S methyl epimers, and 8) has been carried out. The synthetic approach entailed the synthesis of substituted resorcinols, which were subjected to acid catalyzed condensation with trans-para-menthadienol to provide the Δ8-THC analogue. The 1′-, 2′- and 3′-methylheptyl analogues (3–5) are considerably more potent than Δ8-THC. The 4′-, 5′- and 6′-methylheptyl isomers (6–8) are approximately equal in potency to Δ8-THC.The synthesis of eleven isomeric monomethylpheptyl-Δ8-tetrahydrocannabinols has been carried out. Both epimers of the 1′-, 2′- and 3′-methylheptyl analogues were considerably more potent than Δ8-THC, both in vitro and in vivo.