Biomedical subjects

D Papahatjis

Publications and source records attributed to D Papahatjis.

4 recordsLinked to original sources

PubMed2005

Behavioral pharmacological properties of a novel cannabinoid 1',1'-dithiolane delta8-THC analog, AMG-3.

Newly developed cannabinoids may hold the promise of the development of useful and safe drugs. This study aimed to investigate the behavioral effects of the novel 1',1'-dithiolane delta8-HC analogue AMG-3, a cannabinomimetic molecule with high affinity for CB1/CB2 receptors. This analog was chosen for its binding affinity to these receptors, which is higher than that reported for delta8-tetrahydrocannabinol (delta8-THC). Behavioral responses were assessed after the administration of AMG-3 (1, 2, 4, 8 mg/kg, i.p.) in the open field, on the bar test, on the hot plate and in the intracranial self-stimulation procedure. AMG-3 increased the reactivity time on the hot plate in a dose- and time-dependent manner, indicating a long-lasting analgesic effect (at least 24 h). The substance was found dose-dependently to decrease spontaneous motor activity and to induce catalepsy, particularly at the highest dose (8 mg/kg). AMG-3 did not affect the rewarding value of intracranial self-stimulation, except to increase the reward threshold at the highest dose (8 mg/kg). The effects of the highest dose of AMG-3 on spontaneous activity and on the self-stimulation paradigm were completely reversed by pre-treatment with the CB1 receptor antagonist AM-251. These findings indicate that the administration of AMG-3 to rats elicits a specific behavioral profile, most probably associated with the activation of CB1 receptors and without effects indicating abuse potential.

Animals↗

PubMed2001

Differential membrane fluidization by active and inactive cannabinoid analogues.

The effects of the two cannabinomimetic drugs (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]pyranyl-2-(hexyl)-1,3-dithiolane (AMG-3) and its pharmacologically less active 1-methoxy analogue (AMG-18) on the thermotropic and structural properties of dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC) liposomes have been studied by X-ray diffraction and differential scanning calorimetry (DSC). DSC data revealed that the incorporation of the drugs affect differently the thermotropic properties of DPPC. The presence of the more active drug distinctly broadened and attenuated both the pretransition and main phase transition of DPPC bilayers, while the inactive analogue had only minor effects. Small and wide angle X-ray diffraction data showed that the two cannabinoids have different effects on the lipid phase structures and on the hydrocarbon chain packing. The pharmacologically active analogue, AMG-3, was found to efficiently fluidize domains of the lipids in the L(beta)' gel phase, and to perturb the regular multibilayer lattice. In the liquid crystalline L(alpha) phase, AMG-3 was also found to cause irregularities in packing, suggesting that the drug induces local curvature. At the same concentration, the inactive AMG-18 had only minor structural effects on the lipids. At about 10-fold or higher concentrations, AMG-18 was found to produce similar but still less pronounced effects in comparison to those observed by AMG-3. The dose-dependent, different thermotropic and structural effects by the two cannabinoid analogues suggest that these may be related to their biological activity.

1,2-Dipalmitoylphosphatidylcholine↗

PubMed1999

Structure elucidation and conformational properties of synthetic cannabinoids (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibe nzo [b,d]pyranyl)-2-hexyl-1,3-dithiolane and its methylated analog.

The synthetic cannabinoid (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-1-hydroxy-6H-dibenzo[b,d]+ ++pyranyl)-2-hexyl-1,3-dithiolane (AMG-3) is a cannabimimetic molecular probe with one of the highest binding affinities reported to date. Therefore, due to its potential pharmacological importance, its structure was sought to be elucidated and its conformational properties were studied using a combination of 1D, 2D NMR spectroscopy and molecular modelling. The structure of its methylated analog (-)-2-(6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H dibenzo [b,d]pyranyl-1-methoxy)-2-hexyl-1,3 dithiolane (AMG-18), was also studied and its conformational properties were compared with AMG-3. AMG-18 lacks of the phenolic hydroxyl group a strict requirement for cannabimimetic activity and is almost devoid of any biological activity. The conformational analysis studies showed that 1',1' dithiolane ring restricted the orientation preferences of alkyl chain. This may account for the high binding affinity of AMG-3 to cananbinoid receptors. Grid scan search studies showed different preferences of possible adopting dihedral values of phenolic hydroxyl group and its methyl ether. These observations may account for their differences in biological activity.

Cannabinoids↗

PubMed1996

Studies on the thermotropic effects of cannabinoids on phosphatidylcholine bilayers using differential scanning calorimetry and small angle X-ray diffraction.

We have studied the thermotropic properties of a wide variety of cannabinoids in DPPC bilayers. The molecules under study were divided into four classes: (a) classical cannabinoids possessing a phenolic hydroxyl group; (b) delta9-THC metabolites with an additional hydroxyl group on the C ring; (c) non-classical cannabinoids, and (d) cannabinoids with a protected phenolic hydroxyl group. The results showed that the first three groups have similar effects on the thermotropic properties of DPPC bilayers up to x = 0.05 (molar ratio) and that these effects do not parallel their biological activity. For concentrations less than x = 0.01, cannabinoids affect mainly the pretransition temperature in a progressive manner until its final abolishment. At x = 0.05, they further affect the main phase transition by lowering its phase transition temperature and broadening its half width. At high concentrations the thermograms have multiple components, indicating that membranes are no longer homogeneous but rather consist of different domains. At these concentrations cannabinoids with more hydroxyl groups give simpler thermograms. Low concentrations of cannabinoids in group d affect significantly the pretransition temperature, while high concentrations affect only marginally the main phase transition by slightly lowering its temperature and broadening its half width. These results point out the importance of the phenolic hydroxyl group in inducing membrane perturbations. The d-spacing data from our small angle X-ray diffraction experiments show that delta8-THC produces significant structural changes in the lipid bilayer, including the gel-phase tilting angle, the intermolecular cooperativity and the gauche:trans conformer ratio. Conversely, the inactive analog Me-delta8-THC does not cause drastic changes to the bilayer structure.

1,2-Dipalmitoylphosphatidylcholine↗