No description available.

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.)

Delta 9 - tetrahydrocannabinol (Delta 9 - THC), given orally was studied for anticonvulsant activity against electroshock seizures, and for anticonvulsant activity as well as protection from lethality against subcutaneous pentylenetetrazol (PTZ), picrotoxin, and strychnine,and intraperitoneal lidocaine in rats. Delta 9 - THC in a dose-related fashion elevates the threshold for maximal electroshock seizures. A dose of 30 mg/kg of delta 9 - THC provides anticonvulsant activity against maximal PTZ seizures while the same dose does not protect against maximal seizures induced by strychnine or minimal seizures induced by electroshock, PTZ, lidocaine or picrotoxin. Further, delta 9 -THC at 30 mg/kg does not protect against lethality induced by any of the chemical convulsants used. These data indicate that delta 9 - THC has a rather narrow anticonvulsant spectrum of activity involving only maximal electroshock and PTZ seizures. In these respects, delta 9 - THC resembles phenytoin.

Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 6 uppsatser.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1970. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

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Tse Kai Kong. / Thesis submitted in: August 1998. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (leaves 116-122). / Abstract also in Chinese. / ABSTRACT --- p.ii / 摘要 --- p.v / ACKNOWLEDGEMENTS --- p.viii / CONTENTS --- p.ix / LIST OF FIGURES --- p.xiii / LIST OF TABLES --- p.xvii / ABBREVIATIONS --- p.xix / Chapter CHAPTER ONE --- Introduction --- p.1 / Chapter 1 --- Introduction --- p.2 / Chapter 1.1 --- Definition and Prevalence of Epilepsy --- p.2 / Chapter 1.2 --- Neurophysiology and Pathophysiology of Epilepsy --- p.3 / Chapter 1.3 --- Drugs Currently Used in the Treatment of Epilepsy --- p.5 / Chapter 1.4 --- Triazolines Aminoalkylpyridines as a New Class of Potential Antiepileptic Drugs --- p.9 / Chapter 1.5 --- Chemical Synthesis of Aminoalkylpyridines --- p.14 / Chapter 1.6 --- Metabolism of Aminoalkylpyridines --- p.15 / Chapter 1.7 --- Anticonvulsant Activities of Aminoalkylpyridines --- p.16 / Chapter 1.8 --- Aim and Scope of the Present Study --- p.18 / Chapter CHAPTER TWO --- Experimental --- p.19 / Chapter 2.1 --- MATERIALS --- p.20 / Chapter 2.2 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.22 / Chapter 2.2.1 --- Determination of Partition Coefficient --- p.22 / Chapter 2.2.2 --- Determination of Aqueous Solubilities --- p.22 / Chapter 2.2.3 --- Determination of Thermal Properties --- p.23 / Chapter 2.3 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FORp-C1 AMINOALKYLPYRIDINES --- p.24 / Chapter 2.3.1 --- HPLC Apparatus and Conditions --- p.24 / Chapter 2.3.2 --- Animal Treatments and Biological Fluid Collection --- p.24 / Chapter 2.3.3 --- Solid Phase Extraction --- p.25 / Chapter 2.3.4 --- Construction of Calibration Curves for p-Cl AAP in Rat Blood --- p.25 / Chapter 2.3.5 --- Construction of Calibration Curves for p-Cl AAP in Rat Urine --- p.26 / Chapter 2.3.6 --- Accuracy and Precision in the Quantitation of p-C1 AAP in Biological Fluids --- p.26 / Chapter 2.4 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.27 / Chapter 2.4.1 --- Cannulae Preparation --- p.27 / Chapter 2.4.2 --- Dosage --- p.27 / Chapter 2.4.3 --- Animal Surgery and Sample Collection --- p.28 / Chapter 2.4.4 --- Pharmacokinetic Calculations --- p.29 / Chapter 2.5 --- URINARY METABOLIC STUDIES OF p-C1 AAP --- p.30 / Chapter 2.5.1 --- Animal Treatment and Urine Collection --- p.30 / Chapter 2.5.2 --- Deconjugation Assay --- p.30 / Chapter 2.5.3 --- Non-deconjugated Urine Sample Treatment --- p.31 / Chapter 2.5.4 --- Separation of Metabolites by HPLC --- p.31 / Chapter 2.5.5 --- Identification of Metabolites by LC/MS --- p.31 / Chapter 2.5.6 --- Quantitative Analysis --- p.32 / Chapter 2.5.7 --- Preparation of the authentic β-amino alcohol --- p.34 / Chapter 2.6 --- STATISTICAL ANALYSIS --- p.34 / Chapter CHAPTER THREE --- Results and Discussion --- p.35 / Chapter 3.1 --- PREFORMULATION STUDIES ON AMINOALKYLPYRIDINES --- p.36 / Chapter 3.1.1 --- PARTITION COEFFICIENT (K°W) --- p.36 / Chapter 3.1.2 --- AQUEOUS SOLUBILITY --- p.37 / Chapter 3.1.3 --- THERMAL ANALYSIS --- p.41 / Chapter 3.2 --- DEVELOPMENT OF A HIGH PERFORMANCE LIQUID CHROMATOGRAPHIC ASSAY FOR p-C1 AMINOALKYLPYRIDINES --- p.49 / Chapter 3.2.1 --- SOLID PHASE EXTRACTION --- p.49 / Chapter 3.2.2 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT BLOOD --- p.49 / Chapter 3.2.3 --- CONSTRUCTION OF CALIBRATION CURVES FOR p-C1 AAP IN THE RAT URINE --- p.52 / Chapter 3.2.4 --- ACCURACY AND PRECISION IN THE QUANTITATION OF p-Cl IN THE BIOLOGICAL FLUIDS --- p.54 / Chapter 3.3 --- PRELIMINARY PHARMACOKINETICS OF p-C1 AAP FOLLOWING INTRAVENOUS ADMINISTRATION --- p.57 / Chapter 3.4 --- URINARY METABOLIC STUDIES OF p-C1AAP --- p.61 / Chapter 3.4.1 --- QUALITATIVE STUDIES : IDENTIFICATION OF METABOLITES --- p.61 / Chapter 3.4.2 --- QUANTITATIVE STUDIES --- p.94 / Chapter CHAPTER FOUR --- Conclusion --- p.111 / REFERENCES --- p.115 / APPENDIX Published Papers --- p.121

Thesis (M.Phil.) - University of Queensland, 2005. / Includes bibliography.

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