Structural determinants of the partial agonist-inverse agonist properties of 6′-azidohex-2′-yne-Δ8-tetrahydrocannabinol at cannabinoid receptors
Structural determinants of the partial agonist-inverse agonist properties of 6′-azidohex-2′-yne-Δ8-tetrahydrocannabinol at cannabinoid receptors
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DOI：
10.1038/sj.bjp.0702836
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发表时间：
1999-10-01
影响因子：
7.3
通讯作者：
Pertwee, RG
中科院分区：
文献类型：
--
作者：
Ross, RA;Gibson, TM;Pertwee, RG
1我们扩展了以前对Delta（8）-四氢大麻酚（Delta（8）-THC）的四种类似物的研究：6 ′-叠氮基己-2 ′-炔-δ（8）-THC（O-1184），6 ′-叠氮基己-顺-2 ′-烯-δ（8）-THC（O-1238）和辛基-2 ′-炔-δ（8）-THC（O-584）及其I-脱氧类似物（O-1315）。2 O-1184，O-1238和O-584从表达CB 1或CB 2大麻素受体的中国仓鼠卵巢（CHO）细胞膜上的特异性结合位点取代[H-3]-CP 55940，pK（i）值为8.28至8.45（CBi）和8.03至8.13（CB 2）。O-1315的pK（i）值显著较小，分别为7.63（CB 1）和7.01（CB 2）。3所有类似物均抑制毛喉素刺激的CB 1转染的CHO细胞产生环AMP（pEC（50）= 9.16至9.72）。在该细胞系中，只有O-1238表现为完全激动剂。4在小鼠输精管中，O-1238抑制电诱发的收缩（pEC（50）= 10.18和E-max = 70.5%）。O-1184的相应值分别为9.08和21.1%。在1 nM时，O-1184对大麻素受体激动剂CP 55940产生了可克服的拮抗作用。然而，在0.1 nM时，O-1184不会减弱CP 55940诱导的CB（1-）转染CHO细胞对环AMP产生的抑制。5在CB 2转染CHO细胞中，CP 55940抑制环AMP产生（pEC（50）= 8.59），O-1184和O-584对CP 55940有明显的拮抗作用（pEC（50）分别为8.20和6.86），而O-1238和O-1315对CP 55940无明显影响。将CP 55940的pEC（50）从8.61降低至7.42（O-1184）或从8.54降低至7.44（O-1238）。7这些数据支持增加Delta（8）-THC类似物对CB 1或CB 2受体亲和力的影响很小，但可以降低CB 1受体的效力并逆转CB 2受体引起的反应方向。
1 We have extended previous investigations of four analogues of Delta(8)-tetrahydrocannabinol (Delta(8)-THC): 6'-azidohex-2'-yne-Delta(8)-THC (O-1184), 6'-azidohex-cis-2'-ene-Delta(8)-THC (O-1238) and octyl-2'-yne-Delta(8)-THC (O-584) and its I-deoxy-analogue (O-1315).2 O-1184, O-1238 and O-584 displaced [H-3]-CP55940 from specific binding sites on Chinese hamster ovary (CHO) cell membranes expressing CB1 or CB2 cannabinoid receptors, with pK(i) values of 8.28 to 8.45 (CBi) and 8.03 to 8.13 (CB2). The pK(i) values of O-1315 were significantly less, 7.63 (CB1) and 7.01 (CB2).3 All the analogues inhibited forskolin-stimulated cyclic AMP production by CB1-transfected CHO cells(pEC(50) = 9.16 to 9.72). Only O-1238 behaved as a full agonist in this cell line.4 In mouse vasa deferentia, O-1238 inhibited electrically-evoked contractions (pEC(50) = 10.18 and E-max = 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 CB(1-)transfected CHO cells.5 In CB2-transfected CHO cells, cyclic AMP production was inhibited by CP55940 (pEC(50) = 8.59), enhanced by O-1184 and O-584 (pEC(50) = 8.20 and 6.86 respectively) and not significantly affected by O-1238 or O-1315.6 At 100 nM, O-1184 and O-1238 produced surmountable antagonism of CP55940 in CB2 cells, decreasing the pEC(50) of CP55940 from 8.61 to 7.42 (O-1184) or from 8.54 to 7.44 (O-1238).7 These data support the hypothesis that increasing the degree of unsaturation of the aliphatic side-chain of Delta(8)-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.