Importance of the C-1 Substituent in Classical Cannabinoids to CB2 Receptor Selectivity:  Synthesis and Characterization of a Series of O,2-Propano-Δ8-tetrahydrocannabinol Analogs

Reggio, Patricia H.; Wang, Tiansheng; Brown, Amy; Fleming, Denise N.; Seltzman, Herbert H.; Griffin, Graeme; Pertwee, Roger G.; Compton, David R.; Abood, Mary E.; Martin, Billy R.

doi:10.1021/jm970136g

Cited by 18 publications

(5 citation statements)

References 27 publications

(52 reference statements)

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“…78 More recently, in an attempt to separate the euphoric effects of cannabinoids from their potential therapeutic effects, a series of propano-⌬ 8 -THC analogues have been synthesized. 72 These modified classical cannabinoids indicate that the carbon at position one in the molecule may be important in conveying CB2-receptor-selective activation, and they have generated a further CB2-selective research tool.…”

Section: Structure and Functionmentioning

confidence: 99%

Pharmacology and potential therapeutic uses of cannabis

Hirst

Lambert

Notcutt

1998

British Journal of Anaesthesia

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Throughout history, cannabis has been used as a natural therapeutic herb. Indeed the discovery of the remains of a young girl in Jerusalem who died in childbirth sometime around the third century AD, revealed residues of cannabis in the pelvic region. 97 This strongly suggests that cannabis was used in medical practice in early human civilizations. Cannabis was first used as a medicine in Britain in the mid-nineteenth century by O'Shaugnessy, an army surgeon. While in India O'Shaugnessy witnessed at first hand the use of cannabis for a wide range of medical conditions such as rabies, epilepsy and muscle spasms, and for pain relief. On his return to Britain, O'Shaugnessy advocated its use and cannabis was widely accepted as a medicine for about 70 years. 61 63 In this article we shall review the pharmacology of cannabinoids and their therapeutic potential. In particular, we shall discuss their use as antinociceptive/ analgesic agents. The reader is referred to several excellent review articles and books on this subject. 4 8 22 37 45 50 63 69 95 The major psychoactive constituent of Cannabis sativa was first isolated in 1964. 32 The compound was identified as ⌬ 9-tetrahydrocannabinol (⌬ 9-THC, fig. 1), and when administered to humans produced a spectrum of effects, including increased pulse rate, decreased blood pressure, muscle weakening, increased appetite, euphoria followed by drowsiness, depersonalization, altered time sense and decreased memory recollection; hearing became less discriminative and visual signals were sharper but distorted. 45 The effects of ⌬ 9-THC at the biochemical level were virtually unknown until recently. Pharmacological studies suggested that ⌬ 9-THC and other active cannabinoids might act at specific receptor sites, 38 68 but the high lipophilicity of these compounds made their use in binding assays very difficult. Some researchers were initially of the opinion that the effects observed with ⌬ 9-THC were attributable to perturbation of membrane structures. 43 However, these proposals were refuted and early attempts to identify specific cannabinoid receptor binding sites in brain membranes showed encouraging results. 64 As early as 1984, Howlett and co-workers 47 showed that cannabinoids caused inhibition of adenylyl cyclase. It was subsequently shown that this effect

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Section: Structure and Functionmentioning

confidence: 99%

Pharmacology and potential therapeutic uses of cannabis

Hirst

Lambert

Notcutt

1998

British Journal of Anaesthesia

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“…However, the inactive O-methyl analog lacks of this capability. The importance of the C-1 substituent in classical cannabinoids to CB 2 receptor selectivity has been recently studied [12]. We believe that such a system is ideal for studying drugm embrane interactions in general.…”

Section: Introductionmentioning

confidence: 99%

Effects of cannabinoids in membrane bilayers containing cholesterol

Mavromoustakos

Daliani

1999

Biochimica et Biophysica Acta (BBA) - Biomembranes

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The thermotropic and dynamic properties of the biologically active Delta(8)-tetrahydrocannabinol (Delta(8)-THC) and its inactive congener O-methyl-Delta(8)-tetrahydrocannabinol (Me-Delta(8)-THC) in DPPC/cholesterol (CHOL) bilayers have been studied using a combination of DSC and solid-state NMR spectroscopy. The obtained results showed differential effects of the two cannabinoids under study. These are summarized as follows: (a) the presence of the active compound fluidizes more significantly the DPPC/CHOL bilayers than the inactive analog as it is revealed by DSC and NMR spectroscopy results; (b) cholesterol seems to play a significant role in the way cannabinoids act in membrane bilayers; (c) the observed additional peaks in (13)C/MAS-NMR spectra which were cannabinoid specific offer an evidence of their different dynamic properties in membranes. In particular, the aromatic part of the inactive cannabinoid appears more mobile than that of the active one. This finding is in agreement with previously obtained X-ray data which locate the inactive cannabinoid in the hydrophobic core of the bilayer while the active one in the polar region; and (d) the observed downfield shift of C-1 carbon in the preparation containing the active cannabinoid is a strong evidence that Delta(8)-THC resides nearby the polar region where also cholesterol is well known to locate itself. Such downfield shift is absent when Me-Delta(8)-THC is resided in the membrane bilayer. These differential effects of the two cannabinoids propose that the phospholipid/cholesterol core of the membrane may play an important role in the mode of cannabinoid action by regulating their thermotropic and dynamic properties.

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“…Synthesis of a series of ⌬ 8 -THC analogs in which the phenolic hydroxyl at position 1 was removed (deoxy-⌬ 8 -THC analogs) or replaced with a methoxyl resulted in analogs with selectivity for CB 2 receptors (Gareau et al, 1996;Huffman et al, 1996Huffman et al, , 1999. Incorporation of an oxygen into a fourth ring attached at C1 also increased CB 2 selectivity, suggesting possible differences in the interaction of oxygen in the binding pockets of CB 1 and CB 2 receptors (Reggio et al, 1997). In the present study, we examined structure-activity relationships of a series of bicyclic resorcinols in which the core chemical structure contained two hydroxyl substituents positioned with a single intervening carbon on a benzene ring.…”

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confidence: 99%

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists

Wiley

Beletskaya²,

Ng³

et al. 2002

J Pharmacol Exp Ther

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The role of the oxygen of the benzopyran substituent of ⌬ 9 -tetrahydrocannabinol in defining affinity for brain cannabinoid (CB 1 ) receptors is not well understood; however, it is known that opening the pyran ring can result in either increased potency and affinity, as in CP 55,940 [(Ϫ)-cis-3-[2-hydroxy-4(1,1-dimethyl-heptyl)phenyl]-trans-4-(3-hydroxy-propyl)cyclohexanol], or in an inactive cannabinoid, as in cannabidiol. In the present study, a series of bicyclic resorcinols that resemble cannabidiol were synthesized and tested in vitro and in vivo. Analysis of the structure-activity relationships of these analogs revealed several structural features that were important for maintaining CB 1 receptor recognition and in vivo activity, including the presence of a branched lipophilic side chain and free phenols as well as substitution of a cyclohexane as the second ring of these bicyclic cannabinoids. Many of these analogs exhibited CB 2 selectivity, particularly the dimethoxyresorcinol analogs, and this selectivity was enhanced by longer side chain lengths. Hence, unlike cannabidiol, these resorcinol derivatives had good affinity for CB 1 and/or CB 2 receptors as well as potent in vivo activity. These results suggest that the resorcinol series represent a novel template for the development of CB 2 -selective cannabinoid agonists that have the potential to offer insights into similarities and differences between structural requirements for receptor recognition at CB 1 and CB 2 receptors.

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Importance of the C-1 Substituent in Classical Cannabinoids to CB₂ Receptor Selectivity: Synthesis and Characterization of a Series of O,2-Propano-Δ⁸-tetrahydrocannabinol Analogs

Cited by 18 publications

References 27 publications

Pharmacology and potential therapeutic uses of cannabis

Pharmacology and potential therapeutic uses of cannabis

Effects of cannabinoids in membrane bilayers containing cholesterol

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists

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Importance of the C-1 Substituent in Classical Cannabinoids to CB2 Receptor Selectivity: Synthesis and Characterization of a Series of O,2-Propano-Δ8-tetrahydrocannabinol Analogs

Cited by 18 publications

References 27 publications

Pharmacology and potential therapeutic uses of cannabis

Pharmacology and potential therapeutic uses of cannabis

Effects of cannabinoids in membrane bilayers containing cholesterol

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB1/CB2 and CB2-Selective Agonists

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Product

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Importance of the C-1 Substituent in Classical Cannabinoids to CB₂ Receptor Selectivity: Synthesis and Characterization of a Series of O,2-Propano-Δ⁸-tetrahydrocannabinol Analogs

Resorcinol Derivatives: A Novel Template for the Development of Cannabinoid CB₁/CB₂ and CB₂-Selective Agonists