Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents.

Persistent Link:
http://hdl.handle.net/10150/184523
Title:
Synthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents.
Author:
Shah, Vibhakar Jayantilal.
Issue Date:
1988
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Anticonvulsant activity of cannabidiol (CBD) has been well documented in various laboratory animal species and also in man. As part of our continuing effort to study and to define the structure anticonvulsant relationship several analogs of CBD were synthesized wherein its structural units, namely, the terpene ring, aryl ring and/or side chain were systematically modified. These analogs include the: (1) unnatural (+)-Cannabidol (1b), (2) Delta-3-carenyl analog-(+)-carenadiol (45a), its diacetate (45b) and its 1",1"-dimethylheptyl side chain analog (45c), and (3) unnatural 7-acetoxycannabidiol (46b). (+)-Cannabidiol (1b) was synthesized in about 20-25% yield from olivetol (51) and two different p-menthadienols (67 and 70) as monoterpenoid synthons. (-)-p-Mentha-1,8-dien-3-ol (67) was prepared from (-)-limonene (65) by chromium trioxide-pyridine complex oxidation followed by cerium trichloride assisted sodium borohydride reduction of the obtained ketone (66a). (-)-p-Mentha-2,8-dien-1-ol (70) was synthesized from 1:1 mixture of cis- (69a) and trans-epoxide (68a) of limonene (65) in about 35% yield. The reaction involves phenylselenide anion mediated stereospecific trans-diaxial opening of the epoxide ring to give the required alcohol (70) along with its regioisomer (71) as the major product (79%). The delta-3-carenyl analog (+)-carenadiol (45a) was synthesized from car-4-en-3β-ol (80) and olivetol (51) in about 20% yield. Car-4-en-3β-ol (80) was prepared in about 90-95% yield from the corresponding 3β,4β-epoxy carane (77) by following the same methodology described for (70). The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rotorod (ROT) test. A general lack of stereoselectivity for the anti-AGS and ROT neurotoxic effects was observed for CBD and its derivatives. Thus (-)-CBD (1a) was marginally more potent than (+)-CBD (1b). But the CBD analog derived from (+)-car-3-ene (72), i.e., (+)-carenadiol (45a), is of interest because of its high protective index (PI = 5.1) and is therefore comparable to(1b) (to which it is stereochemically related) in potency. The 1",1"-dimethylheptyl derivative ((+)-45b), could not separate anticonvulsant activity from neurotoxicity. (Abstract shortened with permission of author.)
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Cannabinoids.; Anticonvulsants.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Pharmaceutical Sciences; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Martin, Arnold R.

Full metadata record

DC FieldValue Language
dc.language.isoenen_US
dc.titleSynthesis of cannabidiol stereoisomers and analogs as potential anticonvulsant agents.en_US
dc.creatorShah, Vibhakar Jayantilal.en_US
dc.contributor.authorShah, Vibhakar Jayantilal.en_US
dc.date.issued1988en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractAnticonvulsant activity of cannabidiol (CBD) has been well documented in various laboratory animal species and also in man. As part of our continuing effort to study and to define the structure anticonvulsant relationship several analogs of CBD were synthesized wherein its structural units, namely, the terpene ring, aryl ring and/or side chain were systematically modified. These analogs include the: (1) unnatural (+)-Cannabidol (1b), (2) Delta-3-carenyl analog-(+)-carenadiol (45a), its diacetate (45b) and its 1",1"-dimethylheptyl side chain analog (45c), and (3) unnatural 7-acetoxycannabidiol (46b). (+)-Cannabidiol (1b) was synthesized in about 20-25% yield from olivetol (51) and two different p-menthadienols (67 and 70) as monoterpenoid synthons. (-)-p-Mentha-1,8-dien-3-ol (67) was prepared from (-)-limonene (65) by chromium trioxide-pyridine complex oxidation followed by cerium trichloride assisted sodium borohydride reduction of the obtained ketone (66a). (-)-p-Mentha-2,8-dien-1-ol (70) was synthesized from 1:1 mixture of cis- (69a) and trans-epoxide (68a) of limonene (65) in about 35% yield. The reaction involves phenylselenide anion mediated stereospecific trans-diaxial opening of the epoxide ring to give the required alcohol (70) along with its regioisomer (71) as the major product (79%). The delta-3-carenyl analog (+)-carenadiol (45a) was synthesized from car-4-en-3β-ol (80) and olivetol (51) in about 20% yield. Car-4-en-3β-ol (80) was prepared in about 90-95% yield from the corresponding 3β,4β-epoxy carane (77) by following the same methodology described for (70). The compounds were evaluated for anticonvulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rotorod (ROT) test. A general lack of stereoselectivity for the anti-AGS and ROT neurotoxic effects was observed for CBD and its derivatives. Thus (-)-CBD (1a) was marginally more potent than (+)-CBD (1b). But the CBD analog derived from (+)-car-3-ene (72), i.e., (+)-carenadiol (45a), is of interest because of its high protective index (PI = 5.1) and is therefore comparable to(1b) (to which it is stereochemically related) in potency. The 1",1"-dimethylheptyl derivative ((+)-45b), could not separate anticonvulsant activity from neurotoxicity. (Abstract shortened with permission of author.)en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectCannabinoids.en_US
dc.subjectAnticonvulsants.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMartin, Arnold R.en_US
dc.identifier.proquest8902359en_US
dc.identifier.oclc701928247en_US
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