Synthesis and pharmacology of 11-nor-1-methoxy-9-hydroxyhexahydrocannabinols and 11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: New selective ligands for the cannabinoid CB2 receptor

Marriott, Karla‐Sue C.; Huffman, John W.; Wiley, Jenny L.; Martin, Billy R.

doi:10.1016/j.bmc.2005.11.023

Cited by 23 publications

(15 citation statements)

References 22 publications

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“…38 However, none of the CP-47,497 and CP-55,940 analogs (8, 13 and 9, respectively) have high affinity for the CB 1 receptor or better than modest affinity for the CB 2 receptor. For example, the greatest selectivity for the CB 2 receptor (13-fold) is found in JWH-324 (8, n = 5), but this compound still has only modest affinity for the CB 2 receptor with K i = 231 ± 48 nM.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940

Huffman

Thompson

Wiley

et al. 2008

Bioorganic & Medicinal Chemistry

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A series of 1-deoxy analogs of CP-47,497 (8 and 13, n = 0 to 7) and 1-deoxy analogs of CP-55,940 (9, n = 0 to 7) have been synthesized and their affinities for the cannabinoid CB 1 and CB 2 receptors have been determined. Although the majority of these compounds exhibit selectivity for the CB 2 receptor none have greater than modest affinity for either receptor. The interactions of these 1-deoxy nontraditional cannabinoids with the CB 2 receptor are discussed.

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Section: Discussionmentioning

confidence: 99%

Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940

Huffman

Thompson

Wiley

et al. 2008

Bioorganic & Medicinal Chemistry

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“…This may be due to lack of drug-like qualities displayed by this chemotype. However, Huffman and co-workers [142,143] continue to excite the community with improvements in selectivity and new variations on the classic cannabinoid structure. The most studied synthetic classical cannabinoid, as measured by occurrences in the literature, is HU-210 (9; Fig.…”

Section: Classical Cannabinoidsmentioning

confidence: 99%

“…The patent reported several compounds that have full agonist activity (EC 50 values <300 nM; E max values >50%) at the CB2 receptor and limited activity at the CB1 receptor (EC 50 values >1,000 nM; E max values <30%). Although no binding data were offered for individual compounds and no SAR is available, Marriott and co-workers have tried to further understand the SAR of this compound class at the CB2 receptor by the synthesis of 11-nor-1-methoxy-and 11-nor-1-deoxy-9β-hydroxyhexahydrocannabinols (HHC) with 1',1'-dimethylalkyl side chains [143]. These series include compounds that have high affinity for the CB2 receptor, Schering Corporation has further expanded its CB2 receptor ligand space by continuing to explore a number of middle linker groups within their published patent application ranging from simple aryl to indole and azaindoles [146].…”

Section: Indolesmentioning

confidence: 99%

The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists

Whiteside¹,

Lee²,

Valenzano³

2007

CMC

119

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This review gives a brief overview of the expression patterns, molecular pharmacology and physiological role of the cannabinoid 2 receptor (CB2) in pain. Particular emphasis is given to the therapeutic utility of CB2 receptor agonists. Through studies utilizing selective CB2 receptor agonists, non-selective cannabinoid agonists in conjunction with selective CB1 and CB2 receptor antagonists, or CB2 receptor knockout mice, it is now clear that this receptor plays a critical role in nociception. To this end, CB2 receptors have been shown to modulate acute pain, chronic inflammatory pain, post-surgical pain, cancer pain and pain associated with nerve injury. Here we review these studies and the compounds that were utilized. We hypothesize the mechanism of action by which the CB2 receptor could be involved in these processes. Finally we summarize the most recent novel chemical scaffolds that are being investigated towards advancing selective CB2 receptor agonists into the clinic. Many new pharmacological agents have been identified by high throughput screening and small molecule lead discovery and optimization in the past 10 years. It is anticipated that at least some of these agents may ultimately constitute effective new pain therapeutics that lack the side effects associated with traditional cannabinoid ligands.

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“…Until recently, this question could only be approached using selective antagonists for the two receptors. The development of synthetic cannabinoids that are selective for CB2 (Huffman et al 1996; Huffman et al 1999; Huffman et al 2005; Marriott et al 2006) has allowed direct testing of the hypothesis that agonist activation of this receptor down-regulates immune responses. CB2-selective agonists have been shown to be anti-inflammatory and immunosuppressive in mouse models of a wide variety of conditions where immune responses are detrimental, including Experimental Autoimmune Encephalitis (EAE), which is a mouse model of multiple sclerosis (Maresz et al 2007; Zhang et al 2009b), ischemic/perfusion injury following an induced stroke (Ni et al 2004; Zhang et al 2007; Zhang et al 2009a), rheumatoid arthritis (Sumariwalla et al 2004), inflammatory bowel disease (Storr et al 2009), spinal cord injury (Adhikary et al 2011; Baty et al 2008), sepsis (Tschöp et al 2009), autoimmune uveoretinitis (Xu et al 2007), osteoporosis (Ofek et al 2006) and systemic sclerosis (Servettaz et al 2010a).…”

Section: Introductionmentioning

confidence: 99%

Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an In Vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction

Robinson

Meissler

Breslow-Deckman

et al. 2013

J Neuroimmune Pharmacol

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Cannabinoids are known to have anti-inflammatory and immunomodulatory properties. Cannabinoid receptor 2 (CB2) is expressed mainly on leukocytes and is the receptor implicated in mediating many of the effects of cannabinoids on immune processes. This study tested the capacity of Δ9-tetrahydrocannabinol (Δ9-THC) and of two CB2-selective agonists to inhibit the murine Mixed Lymphocyte Reaction (MLR), an in vitro correlate of graft rejection following skin and organ transplantation. Both CB2-selective agonists and Δ9-THC significantly suppressed the MLR in a dose dependent fashion. The inhibition was via CB2, as suppression could be blocked by pretreatment with a CB2-selective antagonist, but not by a CB1 antagonist, and none of the compounds suppressed the MLR when splenocytes from CB2 deficient mice were used. The CB2 agonists were shown to act directly on T-cells, as exposure of CD3+ cells to these compounds completely inhibited their action in a reconstituted MLR. Further, the CB2-selective agonists completely inhibited proliferation of purified T-cells activated by anti-CD3 and anti-CD28 antibodies. T-cell function was decreased by the CB2 agonists, as an ELISA of MLR culture supernatants revealed IL-2 release was significantly decreased in the cannabinoid treated cells. Together, these data support the potential of this class of compounds as useful therapies to prolong graft survival in transplant patients.

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Synthesis and pharmacology of 11-nor-1-methoxy-9-hydroxyhexahydrocannabinols and 11-nor-1-deoxy-9-hydroxyhexahydrocannabinols: New selective ligands for the cannabinoid CB2 receptor

Cited by 23 publications

References 22 publications

Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940

Synthesis and pharmacology of 1-deoxy analogs of CP-47,497 and CP-55,940

The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists

Cannabinoids Inhibit T-cells via Cannabinoid Receptor 2 in an In Vitro Assay for Graft Rejection, the Mixed Lymphocyte Reaction

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