Structural Requirements for Cannabinoid Activity*

Edery, H.; Grunfeld, Yona; Ben‐Zvi, Zvi; Mechoulam, Raphael

doi:10.1111/j.1749-6632.1971.tb13985.x

Cited by 114 publications

(46 citation statements)

References 12 publications

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“…Extensive structure-activity relationship studies began almost immediately after the structure of ⌬ 9 -THC was established (Gaoni and Mechoulam, 1964;Edery et al, 1971;Razdan, 1986). These initial studies firmly established the importance of three structural features of ⌬ 9 -THC: the C9 position, phenolic hydroxyl group, and pentyl side chain.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of Novel Water-Soluble Cannabinoids

Martin

Wiley²,

Beletskaya³

et al. 2006

J Pharmacol Exp Ther

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Presently, there are numerous structural classes of cannabinoid receptor agonists, all of which require solubilization for experimental purposes. One strategy for solubilizing water-insoluble tetrahydrocannabinols is conversion of the phenolic hydroxyl to a morpholinobutyryloxy substituent. The hydrochloride salts of these analogs are water-soluble and active in vivo when administered in saline. The present investigation demonstrated that hydrochloride salts of numerous substituted butyryloxy esters are water-soluble and highly potent. The substitutions include piperidine, piperazine, and alkyl-substituted amino moieties. It was also discovered that incorporation of a nitrogenous moiety in the alkyl side chain increased the pharmacological potency of tetrahydrocannabinol. For example, an analog containing a pyrazole in the side chain (O-2545) was found to have high affinity and efficacy at cannabinoid 1 (CB 1 ) and CB 2 receptors, and when dissolved in saline, it was highly efficacious when administered either intravenously or intracerebroventricularly to mice. A series of carboxamido and carboxylic acid amide analogs exhibited high pharmacological potency, but their hydrochloride salts were not water-soluble. On the other hand, incorporation of imidazoles into the terminus of the side chain led to water-soluble hydrochloride salts that were highly potent when administered in saline to laboratory animals. It is now possible to conduct cannabinoid research with agonists that are water-soluble and thus obviating the need of solubilizing agents.Marijuana has attracted considerable attention for centuries because of its psychotropic and medicinal properties. Early scientific investigations were conducted with either smoked plant material or the plant extract. Needless to say, the synthesis of marijuana's major psychotropic constituent, ⌬ 9 -THC, opened a new era in marijuana research (Gaoni and Mechoulam, 1964). For the first time researchers were able to conduct research in a quantitative fashion because the precise dose of ⌬ 9 -THC could be administered. Unfortunately, ⌬ 9 -THC is a noncrystalline, highly lipophilic compound that requires solubilization with either a surfactant agent or adherence to a water miscible substance (albumin, Tween 80, Emulphor, etc.). This high lipophilicity has placed constraints on the pharmacological evaluation of ⌬ 9 -THC. Even when dissolved in these vehicles, ⌬ 9 -THC has limited solubility and will precipitate if care is not exercised. This cannabinoid will adhere to solid surfaces rather than remain in solution under certain conditions. There is always the concern that the use of different vehicles in separate pharmacological studies may influence the pharmacological effects of ⌬ 9 -THC. Undoubtedly, these challenges in drug solubilization contribute to the vagaries accompanying cannabinoid data collection. Although many of the above vehicles are sufficient for systemic administration of cannabinoids, they present significant challenges for cannabinoid administration int...

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Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization of Novel Water-Soluble Cannabinoids

Martin

Wiley²,

Beletskaya³

et al. 2006

J Pharmacol Exp Ther

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“…Edery et al (1971) reported that in rhesus monkey behavioral tests the replacement of the phenolic hydrogen of delta-9-THC with a methyl group renders the molecule inactive. This inactive cannabinoid, O-methyl-delta-9-THC (figure 7), was selected for comparison in order to assess the importance of the position of the lone pairs of electrons of the phenol oxygen.…”

Section: Refinement Of the Templatementioning

confidence: 99%

“…An observation which emerges from a review of all of these studies is that some cannabinoids can be structurally dissimilar as in delta-9-tetrahydrocannabinol (delta-9-THC) and Abbott 40656 (Rosell et al 1979) and yet can have similar activities; whereas others, which show only slight structural differences as in 10-alpha-OH-delta-8-THC and 10-beta-OH-delta-8-THC (Edery et al 1971). can exhibit dramatic activity differences (figure 1).…”

Section: Introductionmentioning

confidence: 99%

“…Certain regions or conformations of the molecules have been proposed to be important. These regions or conformations include a methyl group in the plane of the aromatic ring, a free phenol, and a free C-4(C-5') aromatic position (Edery et al 1971); the phenolic hydroxyl group (Uliss et al 1975); the side chain (Osgood et al 1978); nonplanarity (Binder et al 1979); and planarity of the molecule (Burstein et al 1983). Stereoselectivity in the activity of the tetrahydrocannabinols has been reported (Dewey et al 1984).…”

Section: Introductionmentioning

confidence: 99%

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Molecular Determinants for Cannabinoid Activity: Refinement of a Molecular Reactivity Template

Reggio

1987

PsycEXTRA Dataset

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“…Additionally, hexahydrocannabinol (3) has attracted considerable attention since clinical tests have shown that these compounds have a similar psychotropic activity to natural ∆ 8 -tetrahydrocannabinol (1). 6 Currently, synthesized ∆ 9 -tetrahydrocannabinol (2) (∆ 9 -THC) and its derivatives have been used as the medicines, Marinol ® and Cesamet, ® for patients with chemotherapy-induced nausea and vomiting (CINV), who have failed to respond adequately to conventional antiemetic treatments. Structurally related perrottetinene (4) and perrottetinenic acid (5) with a bibenzyl cannabinoid nucleus were isolated from the extract of the New Zealand liverwort Radula marginata (Figure 2).…”

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confidence: 99%