Novel Adamantyl Cannabinoids as CB1 Receptor Probes
Journal of Medicinal Chemistry (Impact Factor: 5.45). 04/2013; 56(10). DOI: 10.1021/jm4000775
In previous studies compound 1 (AM411), a 3-(1-adamantyl) analog of the phytocannabinoid (-)-∆(8)-tetrahydrocannabinol (∆(8)-THC) was shown to have improved affinity and selectivity for the CB1 receptor. In this work, we further explored the role of the 1-adamantyl group at the C-3 position in a series of tricyclic cannabinoid analogs modified at the 9-northern aliphatic hydroxyl (NAH) position. Of these, 9-hydroxymethyl hexahydrocannabinol 11 (AM4054) exhibited high CB1 affinity and full agonist profile. In the cAMP assay, the 11-hydroxymethyl cannabinol analog 24 (AM4089) had a partial agonist profile, with high affinity and moderate selectivity for rCB1 over hCB2. In vivo results in rat models of hypothermia and analgesia were congruent with in vitro data. Our in vivo data indicates that 3-(1-adamantyl) substitution, within NAH cannabinergics, imparts improved pharmacological profiles when compared to the corresponding, traditionally used, 3-dimethylheptyl analogs and identifies 11 and 24 as a potential useful in vivo CB1 cannabinergic probes.
Article: Diuretic Effects of Cannabinoids[Show abstract] [Hide abstract]
ABSTRACT: In vivo effects of cannabinoid (CB) agonists are often assessed using four well-established measures: locomotor activity, hypothermia, cataleptic-like effects, and analgesia. The present studies demonstrate that doses of CB agonists that produce these effects also reliably increase diuresis. Diuretic effects of several CB agonists were measured in female rats over 2hrs immediately after drug injection and results were compared to hypothermic effects. Direct-acting CB1 agonists, including Δ(9)-THC, WIN 55,212, AM2389, and AM4054 produced dose-dependent increases in diuresis and decreases in colonic temperature with slightly lower ED50 values for diuresis than for hypothermia. The highest doses of cannabinoid drugs yielded, on average, 26 to 32 g/kg urine; comparable effects were obtained with 10 mg/kg furosemide and 3.0 mg/kg U50 488. Methanandamide, 10.0 mg/kg, had lesser effect than other CB agonists, and the CB2 agonist AM1241, the anandamide transport inhibitor AM404, and the CB antagonist rimonabant did not have diuretic effects. In further studies, the diuretic effects of the CB1 agonist AM4054 were similar in male and female rats, displayed a relatively rapid onset to action, and were dose-dependently antagonized by 30 min pretreatment with rimonabant, but not by the TRPV1 antagonist capsazepine, nor were the effects of WIN 55,212 antagonized by the CB2 antagonist AM630. These data indicate that cannabinoids have robust diuretic effects in rats that are mediated via CB1 receptor mechanisms.Journal of Pharmacology and Experimental Therapeutics 09/2012; 344(1). DOI:10.1124/jpet.112.199331 · 3.97 Impact Factor
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ABSTRACT: The effects of cannabinoid CB1 agonists (including Δ9-tetrahydrocannabinol, the main psychoactive component of marijuana) on attention are uncertain, with reports of impairments, no effects, and occasionally performance enhancements. To better understand these effects, we sought to uncover a role of changing online (within-session) strategy as a possible mediator of the effects of the novel, potent CB1 agonist AM 4054, on a model of sustained attention in male Sprague-Dawley rats. In this operant, two-choice reaction time (RT) task, AM 4054 decreased accuracy in an asymmetric manner; that is, performance was spared on one lever but impaired on the other. Furthermore, this pattern was enhanced by the outcome of the previous trial such that AM 4054 strengthened a win-stay strategy on the "preferred" lever and a lose-shift strategy on the "nonpreferred" lever. This pattern is often found in tests of expectancy; therefore, in a second experiment AM 4054 enhanced expectancy that we engendered by altering the probability of the two stimulus cues. Accuracy was impaired in reporting the less frequent cue, but only after two or more presentations of the more frequent cue. Taking the results of the experiments together, AM 4054 engendered expectancy by increasing the role of previous trial location and outcome on performance of future trials, diminishing stimulus control (and therefore, accuracy). This novel effect of CB1 receptor agonism may contribute to the deleterious effects of cannabinoids on attention. (PsycINFO Database Record (c) 2013 APA, all rights reserved).Experimental and Clinical Psychopharmacology 10/2013; 21(5):416-425. DOI:10.1037/a0033668 · 2.71 Impact Factor
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ABSTRACT: My involvement with the field of cannabinoids spans close to three decades, and covers a major part of my scientific career. It also reflects the robust progress in this initially largely unexplored area of biology. During this period of time, I have witnessed the growth of modern cannabinoid biology, starting from the discovery of its two receptors and followed by the characterization of its endogenous ligands and the identification of the enzyme systems involved in their biosynthesis and biotransformation. I was fortunate enough to start at the beginning of this new era and participate in a number of the new discoveries. It has been a very exciting journey. By covering some key aspects of my work during this period of "modern cannabinoid research," this perspective, in part historical, intends to give an account of how the field grew, the key discoveries, and the most promising directions for the future.Journal of Medicinal Chemistry 04/2014; 57(10). DOI:10.1021/jm500220s · 5.45 Impact Factor
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