To examine the effect of changing the length and branching of the end pentyl chain (C5H11) of anandamide (AN), various analogs 1a-h and 2a-f were synthesized from either the known aldehyde ester 6a or from the alcohol 6b and tested for their pharmacological activity. A reproducible procedure was developed for the conversion of arachidonic acid to 6a or 6b in gram quantities (overall yield 15%). The appropriate tetraene esters 7 were prepared by carrying out a Witting reaction, between 6a and the ylide generated from the phosphonium salt of the appropriate alkyl halide or between the ylide of 6d (prepared from 6a-->6b-->6c-->6d) and the appropriate alkyl aldehydes. They were then hydrolyzed to the corresponding acids and transformed into AN analogs 1 via their acid chlorides then treated with excess ethanolamine. alpha-Alkylation of esters 7 gave compounds 8 which were hydrolyzed to the corresponding acids. These acids via their acid chlorides and subsequent treatment with excess fluoroethylamine gave the target compounds 2. In this way analogs 1e and 2a-c were synthesized from 6d while all the remaining analogs were prepared from 6a. In order to assess the optimal length of the alkyl terminus, analogs 1a-d were prepared and showed moderately high affinities (18-55 nM). However analogs 1a-c failed to produce significant pharmacological effects at doses up to 30 mg/kg. Analog 1d was found to be a weak partial agonist. The reason for the lack of activity in 1a-c is presently not clear. Like the THCs, the branching of the end pentyl chain in AN (1e-h) increased potency both in in vitro and in vivo activities; the dimethylheptyl (DMH) analog 1e was the most potent in the series. Similar alkyl substitutions were carried out in the fluoro-2-methylanandamide series (2a-f), and all of these analogs had high receptor affinities (1-14 nM), the DMH analog 2a being the most potent. With a few exceptions they showed robust pharmacological effects, and AN-like profiles. It was shown that the SAR of the end pentyl chain in AN is very similar to that of THCs. However, the magnitude of enhanced potency observed when the side chain of THC was changed from straight to branched was not observed when the end chain of AN was similarly changed.
1 Cannabinoids have low water solubility, necessitating the use of a solubilizing agent. In this paper we investigated whether a novel water-soluble cannabinoid, 3-(5'-cyano-1',1'-dimethylpentyl)-1-(4-N-morpholinobutyryloxy)-D 8 -tetrahydrocannabinol hydrochloride (O-1057), would interact with cannabinoid receptors when water or saline were used as the only vehicle. 3 O-1057 inhibited forskolin-stimulated cyclic AMP production by both CB 1 -and CB 2 -transfected CHO cells (pEC 50 =9.16 and 9.72 respectively), its potency matching that of CP55940 and exceeding that of D 9 -tetrahydrocannabinol. 4 In the mouse isolated vas deferens, O-1057 inhibited electrically-evoked contractions with pEC 50 and E max values of 9.73 and 76.84% respectively. It was antagonized by 100 nM SR141716A, the pK B of SR141716A against O-1057 (8.90) approximating to that against CP55940 (8.97). 5 O-1057 also behaved as a CB 1 receptor agonist in vivo, reducing mouse spontaneous activity and rectal temperature when injected intravenously and inducing antinociception in the mouse tail¯ick test when given intravenously (ED 50 =0.02 mg kg 71 ), intrathecally, intracerebroventricularly or by gavage. In all these assays, O-1057 was more potent than D 9 -tetrahydrocannabinol and, at 0.1 mg kg 71 i.v., was antagonized by SR141716A (3 mg kg 71 i.v.). 6 These data demonstrate the ability of the water-soluble cannabinoid, O-1057, to act as a potent agonist at CB 1 and CB 2 receptors and warrant investigation of the clinical potential of O-1057 as an analgesic.
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