Drugs derived from cannabinoids. 5. .DELTA.6a,10a,-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains

Winn, Martin; Arendsen, D. L.; Dodge, Patrick W.; Dren, Anthony T.; Dunnigan, Daniel A.; Hallas, Robert; Hwang, K.; Kyncl, J; Lee, Young Ho; Plotnikoff, Nicholas P.; Young, Patrick; Zaugg, Harold E.

doi:10.1021/jm00226a003

Cited by 27 publications

(3 citation statements)

References 8 publications

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“…In the gastrointestinal tract, CB 1 receptors have been involved in the control of intestinal motility in different animal species (Heinemann et al ., 1999; Izzo et al ., 2000) and in humans (Croci et al ., 1998). Recently, cannabinoids have been found to reduce intestinal secretion (Tyler et al ., 2000) and to exert gastroprotective effects against the damage induced by stress (Germanò et al ., 2001), thus confirming previous data obtained with Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC) in pylorus‐ligated rats (Winn et al ., 1976; Rivas‐V & Garcia, 1980).…”

Section: Introductionmentioning

confidence: 99%

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Adami

Frati

Bertini

et al. 2002

British J Pharmacology

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1 The role of cannabinoid (CB) receptors in the regulation of gastric acid secretion was investigated in the rat by means of functional experiments and by immunohistochemistry. 2 In anaesthetized rats with lumen-perfused stomach, the non selective CB-receptor agonist WIN 55,212-2 (0.30 ± 4.00 mmol kg 71 , i.v.) and the selective CB 1 -receptor agonist HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.), dose-dependently decreased the acid secretion induced by both pentagastrin (30 nmol kg 71 h 71 ) and 2-deoxy-D-glucose (1.25 mmol kg 71 , i.v.). By contrast, neither WIN 55,212-2 (1 ± 4 mmol kg 71 , i.v.) nor HU-210 (0.03 ± 1.50 mmol kg 71 , i.v.) did modify histamine-induced acid secretion (20 mmol kg 71 h 71 ). The selective CB 2 -receptor agonist JWH-015 (3 ± 10 mmol kg 71 , i.v.) was ine ective. 3 The gastric antisecretory e ects of WIN 55,212-2 and HU-210 on pentagastrin-induced acid secretion were prevented by the selective CB 1 -receptor antagonist SR141716A (0.65 mmol kg 71 , i.v.) and una ected by the selective CB 2 -receptor antagonist SR144528 (0.65 ± 2 mmol kg 71 , i.v.). 4 Bilateral cervical vagotomy and ganglionic blockade with hexamethonium (10 mg kg 71 , i.v., followed by continuous infusion of 10 mg kg 71 h 71 ) signi®cantly reduced, but not abolished, the maximal inhibitory e ect of HU-210 (0.3 mmol kg 71 , i.v.) on pentagastrin-induced acid secretion; by contrast, pretreatment with atropine (1 mg kg 71 , i.v.) did not modify the antisecretory e ect of HU-210. 5 Immunoreactivity to the CB 1 receptor was co-localized with that of the cholinergic marker choline acetyltransferase in neural elements innervating smooth muscle, mucosa and submucosal blood vessels of rat stomach fundus, corpus and antrum. In contrast, CB 2 receptor-like immunoreactivity was not observed. 6 These results indicate that gastric antisecretory e ects of cannabinoids in the rat are mediated by suppression of vagal drive to the stomach through activation of CB 1 receptors, located on pre-and postganglionic cholinergic pathways. However, the ine ectiveness of atropine in reducing the e ect of HU-210 suggests that the release of non cholinergic excitatory neurotransmitters may be regulated by CB 1 receptors.

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Section: Introductionmentioning

confidence: 99%

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Adami

Frati

Bertini

et al. 2002

British J Pharmacology

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“…Pharmaceutical firms and other entities are actively engaged in synthesizing analogs of the cannabinoids, (Pars et al 1976;Razdan and Dalzell 1976;Razdan et al 1976aRazdan et al , 1976bWinn et al 1976;Kurth et al, 1976), instead of further exploring uses of the natural parent compounds. Patent difficulties and stability problems of the natural derivatives as well as legal and political implications have no doubt played an important role in this decision.…”

Section: Monoterpenoid Chromenesmentioning

confidence: 99%

Ethnomedical, Botanical and Phytochemical Aspects of Natural Hallucinogens

Schultes¹,

Farnsworth²

1980

Botanical Museum Leaflets, Harvard University

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More than 200 species and/ or varieties of higher plants, as well as numerous species of basidiomycetes, are reported in the literature to have been used for their hallucinatory and/ or euphoriant effects. Due to a paucity of research, only a few of these have been confirmed as definitely hallucinogenic in man or animals. This article reviews all of those plants now known to have a scientific basis for producing hallucinogenic effects in man or for which reliable ethnobotanical data are available to indicate that they could be hallucinogenic. Those plants alleged to be hallucinatory, but where substantive proof of this effect may be lacking, are summarily included for completeness arid in the hope of stimulating investigation.The hallucinogens of higher plant origin alone are found in 146 genera in more than 50 families. In virtually every instance in which the active constituents are known, their chemical skeletons are unique to a specific genus or to a very closely related genus.It is interesting to note that of more than 200 species of hallucinogenic plants only two are legally prohibited from use in the United States by Federal law: Cannabis sativa and Tabernanthe Iboga. Two or three others are illegal in a few states.

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“…Indeed, the cannabinoid side chain, which is the focus of this study, has been known to be a key pharmacophore since Adams demonstrated the increased potency of the dimethylheptyl analogue of Δ 6a-10a -THC . More recent studies have further demonstrated the critical role played by side-chain length and conformation in determining pharmacological activity (see refs , −31 for examples). For example, in studies by Martin et al the substitution of the pentyl side chain of the inactive cannabinoid 11-nor,9-COOH-Δ 9 -THC with a dimethylheptyl side chain resulted in an active compound, approximately equipotent to Δ 9 -THC itself.…”

Section: Introductionmentioning

confidence: 99%

QSAR Analysis of Δ⁸-THC Analogues: Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency

Keimowitz

et al. 1999

J. Med. Chem.

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A novel quantitative structure-activity relationship (QSAR) for the side-chain region of Delta(8)-tetrahydrocannabinol (Delta(8)-THC) analogues is reported. A series of 36 side-chain-substituted Delta(8)-THCs with a wide range of pharmacological potency and CB1 receptor affinity was investigated using computational molecular modeling and QSAR analyses. The conformational mobility of each compound's side chain was characterized using a quenched molecular dynamics approach. The QSAR techniques included a modified active analogue approach (MAA), multiple linear regression analyses (MLR), and comparative molecular field analysis (CoMFA) studies. All three approaches yielded consistent results. The MAA approach applied to a set of alkene/alkyne pairs identified the most active conformers as those with conformational mobility constrained within an approximately 8 A radius. MLR analyses (restricted to 15 hydrocarbon side-chain analogues) identified two variables describing side-chain length and terminus position that were able to fit the pharmacological data for receptor affinity with a correlation coefficient for pK(D) of 0.82. While chain length was found to be directly related to receptor affinity, the angle made by the side chain from its attachment point to its terminus (angle defined by C3-C1'-side-chain terminus carbon, see Figure 1) was found to be inversely related to affinity. These results suggest that increased side-chain length and increased side-chain ability to wrap around the ring system are predicted to increase affinity. Therefore, the side chain's conformational mobility must not restrict the chain straight away from the ring system but must allow the chain to wrap back around toward the ring system. Finally, the CoMFA analyses involved all 36 analogues; they also provided data to support the hypothesis that for optimum affinity and potency the side chain must have conformational freedom that allows its terminus to fold back and come into proximity with the phenolic ring.

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Drugs derived from cannabinoids. 5. .DELTA.6a,10a,-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains

Cited by 27 publications

References 8 publications

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Ethnomedical, Botanical and Phytochemical Aspects of Natural Hallucinogens

QSAR Analysis of Δ⁸-THC Analogues: Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency

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Drugs derived from cannabinoids. 5. .DELTA.6a,10a,-Tetrahydrocannabinol and heterocyclic analogs containing aromatic side chains

Cited by 27 publications

References 8 publications

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Gastric antisecretory role and immunohistochemical localization of cannabinoid receptors in the rat stomach

Ethnomedical, Botanical and Phytochemical Aspects of Natural Hallucinogens

QSAR Analysis of Δ8-THC Analogues: Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency

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Product

Resources

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QSAR Analysis of Δ⁸-THC Analogues: Relationship of Side-Chain Conformation to Cannabinoid Receptor Affinity and Pharmacological Potency