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AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice

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Abstract

Rationale

The endocannabinoid signaling system (ECS) has been targeted for developing novel therapeutics since ECS dysfunction has been implicated in various pathologies. Current focus is on chemical modifications of the hexahydrocannabinol (HHC) nabilone (Cesamet®).

Objective

To characterize the novel, high-affinity cannabinoid receptor 1 (CB1R) HHC-ligand AM2389 [9β-hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol in two rodent pre-clinical assays.

Materials and methods

CB1R mediation of AM2389-induced hypothermia in mice was evaluated with AM251, a CB1R-selective antagonist/inverse agonist. Additionally, two groups of rats discriminated the full cannabinergic aminoalkylindole AM5983 (0.18 and 0.56 mg/kg) from vehicle 20 min post-injection in a two-choice operant conditioning task motivated by 0.1% saccharin/water. Generalization/substitution tests were conducted with AM2389, AM5983, and Δ9-tetrahydrocannabinol (Δ9-THC).

Results

Δ9-THC (30 mg/kg)-induced hypothermia exhibited a faster onset and shorter duration of action compared with AM2389 (0.1 and 0.3 mg/kg). AM251 (3 and 10 mg/kg) attenuated/blocked hypothermia induced by 0.3 mg/kg AM2389. In drug discrimination, the order of potency was AM2389 > AM5983 > Δ9-THC with ED50 values of 0.0025, 0.0571, and 0.2635 mg/kg, respectively, in the low-dose condition. The corresponding ED50 values in the high-dose condition were 0.0069, 0.1246, and 0.8438 mg/kg, respectively. Onset of the effects of AM2389 was slow with a protracted time-course; the functional, perceptual in vivo half-life was approximately 17 h.

Conclusions

This potent cannabinergic HHC exhibited a slow onset of action with a protracted time-course. The AM2389 chemotype appears well suited for further drug development, and AM2389 currently is used to probe behavioral consequences of sustained ECS activation.

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Acknowledgements

United States Public Health Service Grants DA 09064, DA 03801, DA 9158, DA 7215, and DA 00152 from the National Institute on Drug Abuse (NIDA) supported the work. We thank R. Gifford as well as the three anonymous reviewers for comments on earlier drafts of the manuscript. We thank NIDA for supplies of (−)-Δ9-THC and Dr. S.K. Vemuri for supplying AM251. Parts of these data were presented at the annual meeting of The International Cannabinoid Research Society Symposium June 25 to 29, 2008, at the MacDonald Aviemore Highland Resort, Aviemore, Scotland (Tai et al. 2008).

Disclosure statement

All authors declare that there is no actual or potential conflict of interest related to this manuscript.

Role of the funding source

Authors declare that the study sponsor did not have any role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

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Authors and Affiliations

  1. Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, 116 Mugar Hall, 360 Huntington Ave, Boston, MA, 02115, USA

    Torbjörn U. C. Järbe, Sherrica Tai, Brian J. LeMay, Spyros P. Nikas, Vidyanand G. Shukla, Alexander Zvonok & Alexandros Makriyannis

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  1. Torbjörn U. C. Järbe
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  2. Sherrica Tai
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  3. Brian J. LeMay
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  6. Alexander Zvonok
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  7. Alexandros Makriyannis
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Correspondence to Torbjörn U. C. Järbe.

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Järbe, T.U.C., Tai, S., LeMay, B.J. et al. AM2389, a high-affinity, in vivo potent CB1-receptor-selective cannabinergic ligand as evidenced by drug discrimination in rats and hypothermia testing in mice. Psychopharmacology 220, 417–426 (2012). https://doi.org/10.1007/s00213-011-2491-1

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