2370-14-1Relevant academic research and scientific papers
BISPHENYL COMPOUNDS USEFUL AS VITAMIN D3 RECEPTOR AGONISTS
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Page/Page column 196-197, (2010/02/14)
The present invention discloses bisphenyl compounds of the formula (I): wherein R1, R2, R3, R4, R5, R6, X, Y, W are defined herein after. These compounds are useful as pharmaceuticals.
Synthesis and pharmacological comparison of dimethylheptyl and pentyl analogs of anandamide
Seltzman, Herbert H.,Fleming, Denise N.,Thomas, Brian F.,Gilliam, Anne F.,McCallion, Deirdre S.,Pertwee, Roger G.,Compton, David R.,Martin, Billy R.
, p. 3626 - 3634 (2007/10/03)
(Dimethylheptyl)anandamide [(16,16-dimethyldocosa-cis-5,8,11,14- tetraenoyl)ethanolamine] (17a) and its amide analogs were synthesized by Wittig coupling of a ylide derived from a fragment of arachidonic acid. These amides were compared to the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide, 2a) and its amide analogs in pharmacological assays for potential enhancement of cannabimimetic activities. The receptor affinity to rat brain membranes of the dimethylheptyl (DMH) analogs increased by an order of magnitude in most comparisons to the corresponding anandamides in displacement assays versus the cannabinoid agonist [3H]CP 55,940 or antagonist [3H]SR141716A, for which rank order differences in affinity were observed. An order of magnitude enhancement of potency with comparable or higher efficacy in behavioral assays in the mouse tetrad of tests of cannabinoid activity was observed in 17a versus 2a. In contrast, no enhancement in potency for the pentyl to DMH side chain exchange was seen in the mouse vas deferens assay. The data indicate a structural equivalence between classical plant cannabinoids and 2a as well as different receptor -ligand interactions that characterize multiple receptor sites or binding modes.
Potent anandamide analogs: The effect of changing the length and branching of the end pentyl chain
Ryan, William J.,Kenneth Banner,Wiley, Jenny L.,Martin, Billy R.,Razdan, Raj K.
, p. 3617 - 3625 (2007/10/03)
To examine the effect of changing the length and branching of the end pentyl chain (C5H11) of anandamide (AN), various analogs la-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 Wittig 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. α-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 la-d were prepared and showed moderately high affinities(18-55 nM). However analogs la-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 la-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 vive 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.
