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Biomedical subjects

R Mechoulam

Publications and source records attributed to R Mechoulam.

At least 127 records · Page 7Linked to original sources
PubMed1987

Stereochemical requirements for cannabimimetic activity.

The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(1S)-delta-3-THC is much more active than (+)-(1R)-delta-3-THC; and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in several animal species resides completely in the (-)-(3R, 4R) enantiomer (32), the difference between the two enantiomers being up to several thousand times. The (3R,4R)-enantiomer (32) is much more active than delta-1- or delta-6-THC in animal tests, the exact level of activity depending on the test employed. The cannabimimetically inactive (+)-(3S,4S) enantiomer (33) was shown to be a potent analgetic in several animal tests. Thus, a complete dissociation between the cannabimimetic and the analgetic effects in a cannabinoid has been achieved, apparently for the first time.

Analgesics↗
PubMed1987

Structure-anticonvulsant activity relationships of cannabidiol analogs.

Cannabidiol (CBD) exhibits anticonvulsant activity in experimental animals and in man. As part of a structure-activity study, analogs were prepared wherein the terpene unit, the aryl unit, and/or the side chain were modified. Thus, several pinenyl and carenyl derivatives, aryl ethers and acetates, and a variety of 1",1"-dialkylhexyl and 1",1"-dialkylheptyl analogs were synthesized. The compounds were evaluated for anti-convulsant activity in seizure susceptible (AGS) rats and for neurotoxicity in the rat rotorod (ROT) test. Comparisons of stereoisomers of CBD and several analogs revealed a general lack of stereoselectivity for anticonvulsant and other CNS properties of this class of compounds.

Animals↗
PubMed1986

Prostaglandins and cannabis XV. Comparison of enantiomeric cannabinoids in stimulating prostaglandin synthesis in fibroblasts.

Stereospecificity has been reported for a number of actions of the cannabinoids in a variety of systems. In the present report, we have shown that this effect can also be demonstrated when human lung fibroblasts in monolayer culture are stimulated by cannabinoids to produce prostaglandin E2 (PGE2). Three enantiomeric pairs of cannabinoids, (+) and (-)-delta 1-tetrahydrocannabinol (THC), (+) and (-)-delta 6-THC and (+) and (-)-delta 6-dimethylheptyl (DMH) THC were tested. In each case the (-) isomer was significantly more potent in agreement with the findings of others using different systems. Interestingly, very little stereospecificity was found in fibroblasts when the release of arachidonic acid, the precursor of PGE2, was monitored. This suggests that cannabinoids may act at several sites within the cell some of which show comparatively greater stereoselectivity for these agonists.

Arachidonic Acid↗
PubMed1986

Cannabimimetic activity (delta 1-THC cue) of cannabidiol monomethyl ether and two stereoisomeric hexahydrocannabinols in rats and pigeons.

Animals (rats and pigeons) trained to discriminate between the presence and absence of the effects of delta 1-tetrahydrocannabinol (delta 1-THC; 3 and 0.56 mg/kg, respectively) were tested for generalization with graded doses of delta 1-THC as well as with two 7-hydroxyhexahydrocannabinol epimers which differ in the stereochemistry at the C-1 position only, and a cannabidiol (CBD)-like compound, cannabidiol monomethyl ether (CBDM). delta 1-THC produced dose/time related effects in both rats and pigeons. Both 7-hydroxyhexahydrocannabinols generalized with delta 1-THC in both species. Greater cannabimimetic activity was observed when the substituent at the C-1 position was equatorial (as in compound NL-105) than when the substituent was axial (compound NL-106) (for chemical structures see Fig. 1, below). Thus in the absence of other substituents the planarity at the C-1 position determines cannabimimetic activity. CBDM induced only vehicle appropriate responding at the doses of 3 and 10 mg/kg in both species; 30% delta 1-THC appropriate responding occurred with 17.5 mg/kg (only tested in pigeons), a dose which also appeared to excert rate depressant effects. Thus, like CBD, CBDM has a low degree of cannabimimetic activity.

Animals↗
PubMed1984

Activity of novel aminocannabinoids in baboons.

The axial and equatorial isomers of 7-(methylamino)hexahydrocannabinol (1 and 2) and 7-(dimethylamino)hexahydrocannabinol (3 and 4) were prepared by reductive amination of the corresponding cannabinoid aldehydes. The amines caused some tranquility in baboons but did not evoke the typical cannabimimetic syndrome caused by psychoactive cannabinoids. However the axial amines (1 and 3) but not the equatorial ones (2 and 4) caused bouts of scratching and yawning. The latter is a rare pharmacological effect hitherto not observed with other cannabinoids.

Animals↗
PubMed1982

Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice.

In mice, running, clonic and tonic convulsions and lethality were assessed following transcorneal (electroshock) current or convulsant drugs, each administered alone and after cannabidiol (CBD) pretreatment. CBD prevented tonic convulsions caused by a convulsant current (CC) 99.99, and by the convulsant dose (CD) 99.99 values of gamma-aminobutyric acid (GABA) inhibitors, 3-mercaptoproprionic acid (3MPA), picrotoxin (PIC), isonicotinic acid hydrazine (INH), pentylenetetrazol (PTZ) and bicuculline (BIC). Rankorder potencies, based on the antitonic ED50 of CBD, were: 3MPA greater than PIC = current = PTZ = BIC. Further, CBD prevented 3MPA-induced lethality, but failed to prevent the occurrence of the other behavioral endpoints of the above treatments. CBD also failed to prevent convulsions and lethality caused by the CD 99.99 of strychnine, a glycine antagonist. The differential effects of CBD suggest that the cannabinoid acts to inhibit seizure spread in the CNS by an action on GABA, but not glycine, mechanisms.

Animals↗
PubMed1982

Anticonvulsant effects of the (-) and (+)isomers of cannabidiol and their dimethylheptyl homologs.

The anticonvulsant actions of the (-) and (+)isomers of cannabidiol and dimethylheptyl-cannabidiol were studied with the maximal electroconvulsive shock model in mice. The ratio of the times for hindlimb extension and fore limb flexion was recorded as an anticonvulsant index. All the cannabinoids were anticonvulsant. They also potentiated pentobarbitone sleeping time. The (+)isomer was more active than the (-)isomer. Possible mechanisms of actions on receptors or membranes are discussed.

Animals↗
PubMed1981

Antiparasitic structure-activity relationships of congocidine derivatives.

Several congocidine analogs were synthesized and tested for in vivo activity against Trypanosoma congolense and in vitro activity against amastigotes of Leishmania tropica. The tripyrrole derivative, beta-([N-methyl-4-[N-methyl-4-(guanidinoacetamido)pyrrole-2-carboxamido]pyrrole -2-carboxamido]pyrrole-2-carboxamido)butyroamidine dihydrochloride, was less toxic and more active than congocidine. The guanidinoacetyl moiety appears to be a structural requirement for antiparasitic activity in the congocidine series.

Animals↗
PubMed1981

A repeated test procedure to assess onset and duration of the cue properties of (-) delta 9-THC, (-) delta 8-THC-DMH and (+) delta 8-THC.

Rats were trained in a two-lever operant box in drug discrimination procedure to respond differentially to the effects induced by 3 mg/kg of (-) delta 9-tetrahydrocannabinol (delta 9-THC) and the drug vehicle. Tests with (-) delta 9-THC and the dimethyl-heptyl (DMH) homologue of (-) delta 8-THC indicated that (-) delta 8-THC-DMH was more potent but had a slower onset of action than (-) delta 9-THC. Two ways of testing the onset and duration of action were compared. In one procedure (separate tests) the time course of the drug action was established by testing each time interval on separate days with a new injection each test day, whereas in the other procedure (repeated tests) all intervals were evaluated after a single injection. The results were similar for both procedures. The median time intervals for the decay of the (-) delta 9-THC stimulus were 122 and 127 min for the separate and repeated tests procedures respectively. The median time intervals for the onset of action of the (-) delta 9-THC-like effects of (-) delta 8-THC-DMH were 65 and 62 min for the separate and repeated tests procedures respectively. The median time intervals for the decay of (-) delta 8-THC-DMH (0.30 and 0.56 mg/kg) was between 8 and 24h after injection. Furthermore, a stereoselective action is indicated, as (+) delta 8-THC (5.6 and 10 mg/kg) did not substitute for (-) delta 9-THC.

Animals↗
PubMed1980

Reduction of hippocampal acetylcholine turnover in rats treated with (-)-delta 8-tetrahydrocannabinol and its 1',2'-dimethyl-heptyl homolog.

The effects of (-)-delta 8-tetrahydrocannabinol (THC), (+)-delta 8-THC, and the dimethyl-heptyl (DMH) homolog of (-)-delta 8-THC (delta 8-THC-DMH) have been compared with the action of (-)-delta 9-THC on the turnover rate of acetylcholine in various brain areas. The data demonstrate that (-)-delta 8-THC-DMH, (-)-delta 9-THC and (-)- delta 8-THC all specifically reduce ther turnover rate of acetylcholine in the hippocampus in a dose-dependent manner ((-)-delta 8-THC-DMH > (-)-delta 9-THC > (-)-delta 8-THC) without altering the acetylcholine or choline content (except for high doses of (-)-delta 8-THC-DMH). The (+)-isomer of delta 8-THC fails to change any cholinergic parameter. The selectivity of action suggests that the tetrahydrocannabinoids may activate specific transmitter receptors which indirectly modulate the activity of the cholinergic neurons in the septal-hippocampal pathway.

Acetylcholine↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics III: preparation of distamycin and congocidine derivatives based on 2,5-disubstituted pyrroles.

Isomers of distamycin A and tripyrrole congocidine containing 2,5-disubstituted pyrroles were synthesized along with distamycin and congocidine homologs containing a single pyrrole ring. Selected compounds were evaluated for their cytotoxicity and antiviral activity. All of the tripyrrole derivatives tested in this series were nontoxic but were less active than distamycin A. The monopyrrole derivative, N-methyl-5-nitropyrrole-2-carboxamido-beta-propionamidine hydrochloride, was nontoxic and was almost as active antivirally as distamycin A.

Antiviral Agents↗
PubMed1980

Cannabidiol and phenytoin: a structural comparison.

Conformational energy maps have been computed for the antiepileptic agents phenytoin and cannabidiol by the quantum-mechanical method of perturbative configuration interaction with localized orbitals (PCILO). The computation indicates that the spatial relationship between the two rings in the two drugs is similar and close to the respective structures in the crystal. This is supported by 1H and 13C NMR measurements. Hence, both compounds fulfill the stereochemical requirements suggested for anticonvulsant drug action.

Cannabidiol↗
PubMed1980

Stereochemical requirements for cannabinoid activity.

Several pairs of cannabinoid isomers were synthesized and tested for psychotropic activity in rhesus monkeys. Two regularities were observed: (a) In the absence of the other substituents, the equatorial stereochemistry of the substituent at C-1 determines activity. (b) Two groups of THC-type cannabinoids which differ only in that the chemical groupings in one of them at C-1, C-2 are situated at C-1, C-6 in the other (but retain their stereochemistry) have almost equivalent psychotropic activity.

Animals↗
PubMed1980

Structure-activity relationships of pyrrole amidine antiviral antibiotics. 2. Preparation of mono- and tripyrrole derivatives of congocidine.

Representatives of three types of congocidine (1) analogues were synthesized. These were tested for cytotoxicity, inhibition of herpes simplex virus (HSV) replication in cultured cells, and effects on the synthesis of HS DNA in isolated nuclei in vitro, as well as on DNA synthesis by purified HSV DNA polymerase. All synthesized tripyrrole derivatives of congocidine were less cytotoxic and more active than the parent drug in all the three ant iviral tests.

Antiviral Agents↗
PubMed1980

Chronic administration of cannabidiol to healthy volunteers and epileptic patients.

In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

Adult↗