We have extended previous investigations of four analogues of Δ8‐tetrahydrocannabinol (Δ8‐THC): 6′‐azidohex‐2′‐yne‐Δ8‐THC (O‐1184), 6′‐azidohex‐cis‐2′‐ene‐Δ8‐THC (O‐1238) and octyl‐2′‐yne‐Δ8‐THC (O‐584) and its 1‐deoxy‐analogue (O‐1315). O‐1184, O‐1238 and O‐584 displaced [3H]‐CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pKi values of 8.28 to 8.45 (CB1) and 8.03 to 8.13 (CB2). The pKi values of O‐1315 were significantly less, 7.63 (CB1) and 7.01 (CB2). All the analogues inhibited forskolin‐stimulated cyclic AMP production by CB1‐transfected CHO cells (pEC50=9.16 to 9.72). Only O‐1238 behaved as a full agonist in this cell line. In mouse vasa deferentia, O‐1238 inhibited electrically‐evoked contractions (pEC50=10.18 and Emax=70.5%). Corresponding values for O‐1184 were 9.08 and 21.1% respectively. At 1 nM, O‐1184 produced surmountable antagonism of the cannabinoid receptor agonist, CP55940. However, at 0.1 nM, O‐1184 did not attenuate CP55940‐induced inhibition of cyclic AMP production by CB1‐transfected CHO cells. In CB2‐transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC50=8.59), enhanced by O‐1184 and O‐584 (pEC50=8.20 and 6.86 respectively) and not significantly affected by O‐1238 or O‐1315. At 100 nM, O‐1184 and O‐1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC50 of CP55940 from 8.61 to 7.42 (O‐1184) or from 8.54 to 7.44 (O‐1238). These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side‐chain of Δ8‐THC analogues has little effect on CB1 or CB2 receptor affinity but can reduce CB1 receptor efficacy and reverse the direction of responses elicited at CB2 receptors. British Journal of Pharmacology (1999) 128, 735–743; doi:
The role of the oxygen of the benzopyran substituent of ⌬ 9 -tetrahydrocannabinol in defining affinity for brain cannabinoid (CB 1 ) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(Ϫ)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB 1 receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB 2 selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB 1 and/or CB 2 receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB 2 -selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB 1 and CB 2 receptors.
A number of side‐chain analogues of Δ8‐THC were tested in GTPγS binding assay in rat cerebellar membranes. O‐1125, a saturated side‐chain compound stimulated GTPγS binding with an Emax of 165.0%, and an EC50 of 17.4 nM. O‐1236, O‐1237 and O‐1238, three‐enyl derivatives containing a cis carbon‐carbon double bond in the side‐chain, stimulated GTPγS binding, acting as partial agonists with Emax values ranging from 51.3–87.5% and EC50 values between 4.4 and 29.7 nM. The stimulatory effects of O‐1125, O‐1236, O‐1237 and O‐1238 on GTPγS binding were antagonized by the CB1 receptor antagonist SR 141716A. The KB values obtained ranged from 0.11–0.21 mM, suggesting an action at CB1 receptors. Five‐ynyl derivatives (O‐584, O‐806, O‐823, O‐1176 and O‐1184), each containing a carbon‐carbon triple bond in the side‐chain, did not stimulate GTPγS binding and were tested as potential cannabinoid receptor antagonists. Each ‐ynyl compound antagonized the stimulatory effects of four cannabinoid receptor agonists on GTPγS binding. The KB values obtained, all found to be in the nanomolar range, did not differ between agonists or from cerebellar binding affinity. In conclusion, alterations of the side‐chain of the classical cannabinoid structure may exert a large influence on affinity and efficacy at the CB1 receptor. Furthermore, this study confirms the ability of the GTPγS binding assay to assess discrete differences in ligand efficacies which potentially may not be observed using alternative functional assays, thus providing a unique tool for the assessment of the molecular mechanisms underlying ligand efficacies. British Journal of Pharmacology (1999) 126, 1575–1584; doi:
The photolysis of 3-(4-tolyl)-3-(trifluoromethyl)diazirine in the presence of benzene, methanol, carbon tetrachloride, cyclohexane, triethylsilane, or diethylamine led to photoproducts consistent with the intermediacy of a singlet carbene. In the case of diethylamine, the photoinsertion into the N-H bond of diethylamine produced the expected adduct, 1-(diethylamino)-2,2,2-trifluoro-1-(4-tolyl)ethane. However, the base-catalyzed elimination of hydrogen fluoride from this adduct afforded an enamine, alpha-(diethylamino)-beta,beta-difluoro-4-methylstyrene, and the subsequent hydrolysis of this enamine furnished diethylamine and 2,2-difluoro-1-(4-tolyl)ethanone. This elimination and hydrolysis sequence effectively reversed the photoinsertion process. A similar photoinsertion and hydrolysis process using 3-(4-n-octylphenyl)-3-(trifluoromethyl)diazirine also produced 2,2-difluoro-1-(4-n-octylphenyl)ethanone in modest yield. These results suggest that the photoinsertion products from 3-aryl-3-(trifluoromethyl)-diazirines in biological systems may suffer similar fates limiting, in part, their utility in obtaining primary sequence data.
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