Synthesis of a bifunctional cannabinoid ligand

Tius, Marcus A.

doi:10.1039/a704889k

Cited by 23 publications

(16 citation statements)

References 14 publications

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“…Further refinement of the CC/NCC hybrids was obtained by imposing restricted rotation around this SAH pharmacophore which was accomplished through the introduction of double and triple bonds at the C2'' position of the 6β-hydroxypropyl chain (13). This promising class of compounds encompassing four asymmetric centers is amongst the most structurally complex and potent cannabinergics synthesized to date [83][84][85][86][87][88][89].…”

Section: Hybrid Cannabinoidsmentioning

confidence: 99%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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The CB1 receptor is expressed in the central nervous system and numerous other tissues including heart, lung and uterus and has been recognized as an important therapeutic target for pain, appetite modulation, glaucoma, multiple sclerosis and other indications. An interesting feature of this GPCR is its ability to be activated by a number of structurally different classes of compounds, thus, raising the possibility of multiple activated forms of the receptor. Understanding of the structure-activity relationships of cannabinergic ligands has paved the road for the development of novel ligands exhibiting receptor subtype selectivity and efficacy. This review highlights the important CB1 cannabinergic ligands developed to date.

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Section: Hybrid Cannabinoidsmentioning

confidence: 99%

CB1 Cannabinoid Receptor Ligands

Thakur¹,

Nikas²,

Makriyannis³

2005

MRMC

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“…The published route towards 7 involves organolithiuma ddition to Weinreb amide 3 (62 %y ield), TiMe 2 Cl 2 -mediated conversion of ketone 6 into the corresponding geminal dimethyl derivative as described by Reetz [26] and subsequent globale ther cleavage with BBr 3 to afford 7 (84 %y ield over two steps). [27] We found that 6 could be conveniently prepared by Fe(acac) 3 -catalyzed (acac = acetylacetonate) cross-coupling [28] of readily availablea cyl chloride 4 and Grignardr eagent 5 [29] in 90 %y ield ( % 12.3 g). In our hands, subsequent conversion of ketone 6 into its geminal dimethyl derivative using TiMe 2 Cl 2 (generated in situ from TiCl 4 and ZnMe 2 )p roceeded in 34 %y ield.…”

Section: Resultsmentioning

confidence: 95%

Highly Selective, Amine-Derived Cannabinoid Receptor 2 Probes

Westphal¹,

Sarott²,

Zirwes³

et al. 2019

Preprint

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The endocannabinoid (eCB) system is implied in various human diseases ranging from central nervous system to autoimmune disorders. Cannabinoid receptor 2 (CB2R) is an integral component of the eCB system. Yet, the downstream effects elicited by this G protein-coupled receptor upon binding of endogenous or synthetic ligands are insufficiently understood—likely due to the limited arsenal of reliable biological and chemical tools. Herein, we report the design and synthesis of CB2R-selective cannabinoids along with their in vitro pharmacological characterization (binding and functional studies). They combine structural features of HU-308 and AM841 to give chimeric ligands that emerge as potent CB2R agonists with high selectivity over the closely related cannabinoid receptor 1 (CB1R). The synthesis work includes convenient preparation of substituted resorcinols often found in cannabinoids. The utility of the synthetic cannabinoids in this study is showcased by preparation of the most selective high-affinity fluorescent probe for CB2R to date.

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“…3) proved to be a potent CB1 agonist [135] and the bulky adamantyl-∆ 8 -THC (AM-411; 11; Fig. The presence of ethers and unsaturations [132,137] within the chain or cyano, azido, carboxamido, and halogen groups at the terminus are also well tolerated [117,[138][139][140][141][142][143][144] (e.g. These investigations suggested the presence of a subsite within the ligand occupied CB1/CB2 binding domain within which side chain substituents immediately adjacent to the aromatic ring may fit.…”

Section: A) Classical and Non-classical Cannabinoidsmentioning

confidence: 99%

“…The preference for the 9β relative configuration has been used for the design and synthesis of high affinity photoactivatable probes for the cannabinoid receptors (e.g. This pharmacophore is referred to as the southern aliphatic hydroxyl group (SAH) [115,142,[162][163][164][165]. 4) [117].…”

Section: A) Classical and Non-classical Cannabinoidsmentioning

confidence: 99%

Cannabinoid Receptors as Therapeutic Targets

Pavlopoulos¹,

Thakur²,

Nikas³

et al. 2006

CPD

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The cannabinoid receptors CB1 and CB2 are family A, G-protein Coupled Receptors that mediate the effects of cannabinoids, a class of compounds that are so named because the first members were isolates of the cannabis plant. In recent history, there has been much anecdotal evidence that the potent and diverse physiological responses produced by these compounds can be turned to therapeutic benefit for a wide variety of maladies. The remarkable abundance of cannabinoid receptors and the discovery of several endogenous ligands along with enzyme and transporter proteins for which they are substrates, suggests that an endogenous cannabinoid neuromodulatory system is an important mediator of biological function. For these reasons CB1 and CB2 receptors are attractive targets for the design of therapeutic ligands. The action of these receptors, however, may also be modulated by manipulating the enzymes and membrane transporters that regulate the endogenous ligands. Despite the range of physiological processes and activities that are mediated by cannabinoid receptors, it is clear that it is possible to produce ligands that result in differential responses. In this paper, we review the pharmacophoric elements that lead to these differential responses and in order to discuss them in context we present an overview of structural aspects governing cannabinoid receptor function, the cannabinergic system and its physiological functions.

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Synthesis of a bifunctional cannabinoid ligand

Cited by 23 publications

References 14 publications

CB1 Cannabinoid Receptor Ligands

CB1 Cannabinoid Receptor Ligands

Highly Selective, Amine-Derived Cannabinoid Receptor 2 Probes

Cannabinoid Receptors as Therapeutic Targets

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