Pharmacophoric Requirements for the Cannabinoid Side Chain. Probing the Cannabinoid Receptor Subsite at C1‘

Abstract

Earlier work from our laboratories has provided evidence for the existence of a subsite within the CB1 and CB2 cannabinoid receptor binding domain corresponding to substituents at the benzylic side chain position of classical cannabinoids. The existence and stereochemical features of this subsite have now been probed through the synthesis of a novel series of (-)-Delta(8)-tetrahydrocannabinol analogues bearing C1'-ring substituents. Of the compounds described here, those with C1'-dithiolane (1c), C1'-dioxolane (2d), and cyclopentyl (2a) substituents exhibited the highest affinities for CB1 and CB2. We used molecular modeling approaches to better define the stereochemical limits of the putative subsite. In vitro pharmacological testing found 1c to be a potent CB1 agonist.

The role of halogen substitution in classical cannabinoids: A CB1 pharmacophore model

“…This observation is congruent with the presence of a hydrophobic subsite at CB1 as has been discussed in our earlier publications. 26,36,37 However, the situation is very different in the 1'-iodo-analog (36), where the presence of one iodo group results in a severe reduction in affinity for the CB1 receptor. This finding reflects either the inability of the CB1 subsite to accommodate a large group such as an iodo substituent or the effect that the halogen may have on the preferred conformation of the side chain.…”

“…The enhanced affinities of all C1'-dimethyl substituted analogs can be attributed to their interaction with a respective subsite within the CB1 binding site as discussed in our earlier publications. 26,36,37 An additional reason for these enhanced affinities may be related to the preferred conformations of these ligands around the C3-C1' bond. As shown in Table 2, in the absence of the two 1',1'-methyl groups in 17a, the C2-C3-C1'-C2' dihedral angle is approximately ±90 degrees.…”

Natural cannabinoids: Templates for drug discovery

“…To optimize the steric contribution due to C-1V substitution, Papahatjis et al synthesized novel analogues (Fig. 9,[42][43][44][45][46][47] in which the 1V,1V-dimethyl group was replaced with 3-to 6-membered heterocyclic and carbocyclic rings (Papahatjis et al, 1998(Papahatjis et al, , 2001(Papahatjis et al, , 2002(Papahatjis et al, , 2003. The most interesting compounds which resulted from this work were the C-1V-dithiolane analogue 43 and C-1V-dioxolane analogue 44.…”

Functional Activity and Switching of Novel Cannabinergic Ligands

“…239 In an attempt to exploit the apparent hydrophobic binding pocket that exists along with the C-3 substituent binding pocket a series of C-1′ cyclic compounds were synthesized (Figure 3.6) for testing. 245 This hydrophobic pocket is evidenced by the fact that 1′,1′-dimethyl compounds bind with far greater affinity than their methylene brethren, and further demonstrated by the lack of binding affinity for the 1′-hydroxyl (42 245 This is an example, though, of a means to gain a 5-fold selection for CB1 over CB2 receptor subtypes. This auxiliary hydrophobic pocket is not a primary binding pocket, as evidenced in the C-1′-dithiolane derivative that is without an additional C-1′ substituent (49) (CB1 Ki = 168 nM; CB2 Ki = 103 nM).…”

“…This auxiliary hydrophobic pocket is not a primary binding pocket, as evidenced in the C-1′-dithiolane derivative that is without an additional C-1′ substituent (49) (CB1 Ki = 168 nM; CB2 Ki = 103 nM). 245 There is some loss of affinity when the C-1′ contains both dithiolane and cylcohexyl substituents (50) (CB1 Ki = 1.86 nM; CB2 Ki = 1.05 nM), suggesting that there exists a balance to be struck between hydrophobic binding and steric bulk too near the benzchromene core (Figure 3.6). However, this same C-1′-cyclohexyl in conjunction with the 1′,1′-dimethyl results in one of the strongest nonselective binding compounds to date (51) (CB1 Ki = 0.57 nM; CB2 Ki = 0.65 nM).…”