POTENT ANANDAMIDE ANALOGS - THE EFFECT OF CHANGING THE LENGTH AND BRANCHING OF THE END PENTYL CHAIN

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 reproducib le procedure was developed for the conversion of arachidonic acid to 6 a or 6b in gram quantities (overall yield 15%). The appropriate tetrae ne esters 7 were prepared by carrying out a Wittig reaction, between 6 a 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 hydroly zed to the corresponding acids and transformed into AN analogs 1 via t heir acid chlorides then treated with excess ethanolamine. alpha-Alkyl ation of esters 7 gave compounds 8 which were hydrolyzed to the corres ponding acids. These acids via their acid chlorides and subsequent tre atment with excess fluoroethylamine gave the target compounds 2. In th is way analogs 1e and 2a-c were synthesized from 6d while all the rema ining analogs were prepared from 6a. In order to assess the optimal le ngth of the alkyl terminus, analogs 1a-d were prepared and showed mode rately high affinities (18-55 nM). However analogs 1a-c failed to prod uce significant pharmacological effects at doses up to 30 mg/kg. Analo g 1d was found to be a weak partial agonist. The reason for the lack o f activity in 1a-c is presently not clear. Like the THCs, the branchin g of the end pentyl chain in AN (1e-h) increased potency both in in vi tro and in vivo activities; the dimethylheptyl (DMH) analog 1e was the most potent in the series. Similar alkyl substitutions were carried o ut in the fluoro-2-methylanandamide series (2a-f), and all of these an alogs had high receptor affinities (1-14 nM), the DMH analog 2a being the most potent. With a few exceptions they showed robust pharmacologi cal effects, and AN-like profiles, It was shown that the SAR of the en d pentyl chain in AN is very similar to that of THCs. However, the mag nitude of enhanced potency observed when the side chain of THC was cha nged from straight to branched was not observed when the end chain of AN was similarly changed.