The conformation of (-)-8α- and (-)-8α-hydroxy-Δ9-tetrahydrocannabinols and their interactions with model membranes.

8α- and 8β-Hydroxy-δ9-tetrahydrocannabinols (THC's), two metabolites of the naturally occurring δ9-THC have been shown to possess differences in pharmacological activity. We have studied the conformations of these two compounds, as well as their interactions with model membrane systems and compared them with δ9-THC. The conformational study, carried out in solution and using high resolution NMR indicated that differences in the ring conformations of these two compounds were negligible butthat the 8-hydroxy group of the 8β-OH compound extended approximately 1.4Å higher above the plane of the aromatic ring than in the 8α-OH isomer. This difference could prove significant in the interaction of these molecules with lipid bilayers. We found that both 8α- and 8β-OH analogs affected the melting behavior of hydrated DPPC bilayers including a lowering of the main transition temperature (Tc), a broadening of that transition and the abolishment of the pretransition of DPPC. The effects of the more active compound, 8β-OH-δ9-THC on the model membrane approximated closely those of δ9-THC, while the less active 8α-OH epimer produced different thermotropic changes

3D-QSAR and docking studies of pentacycloundecylamines at the sigma-1 (σ1) receptor

Pentacycloundecylamine (PCU) derived compounds have been shown to be promising lead structures for the development of novel drug candidates aimed at a variety of neurodegenerative and psychiatric diseases. Here we show for the first time a 3D quantitative structure–activity relationship (3D-QSAR) for a series of aza-PCU-derived compounds with activity at the sigma-1 (r1) receptor. A comparative molecular field analysis (CoMFA) model was developed with a partial least squares cross validated (q2) regression value of 0.6, and a non-cross validatedr2 of 0.9. The CoMFA model was effective at predicting the sigma-1 activities of atest set with an r2 >0.7. We also describe here the docking of the PCU-derivedcompounds into a homology model of the sigma-1 (r1) receptor, which was developed to gain insight into binding of these cage compounds to the receptor. Based on docking studies we evaluated in a [3H]pentazocine binding assay anoxa-PCU, NGP1-01 (IC50 = 1.78 lM) and its phenethyl derivative (IC50 = 1.54 lM). Results from these studies can be used to develop new compounds with specific affinity for the sigma-1(r1)Web of Scienc

Electron-Induced (EI) Mass Fragmentation is Directed by Intra- molecular H-Bonding in Two Isomeric Benzodipyran Systems

The striking differences observed in the electron-induced (EI) mass fragmentationpathways of two isomeric benzodipyrans are attributable to hydrogen bonding in thesemolecules. In the "angular" isomer, 6-butyryl-5-hydroxy-2,2,8,8-tetramethyl-3,4,9,10-tetra-hydro-2H,8H-benzo[1,2-b:3,4-b1]dipyran (2), H-bonding occurs between the aromatic OHgroup and the alpha carbonyl moiety contained in the ortho-phenone group, whereas in the"linear" isomer, 10-butyryl-5-hydroxy-2,2,8,8-tetramethyl-3,4,6,7-tetrahydro-2H,8H-benzo-[1,2-b:5,4-b1]dipyran (3), the aromatic OH group is para to the phenone moiety, effectivelyprecluding any H-bonding. Semi-empirical molecular orbital calculations (AM1) were used tocompare predicted sites of ionization with associated fragmentation patterns. In bothmolecules, the highest occupied molecular orbital (HOMO) was located predominantly on thearomatic moiety. Similarly, in the radical cation species of both compounds, maximum spindensity was located over the aromatic rings. Neither the HOMO nor the spin density mapsprovided a rational explanation for the differences in fragmentation patterns of the twobenzodipyran isomers. The H-bonding favors EI alpha aromatic ring C-O bond cleavage in the"angular" benzodipyran and in 5,7-dihydroxy-2,2-dimethyl-8-butyryl chroman (1), a relatedmonochroman also containing a hydrogen proximal to the aromatic ring C-O bond. In contrast,fragmentation of the "linear" benzodipyran followed a different route, which was exhibited byits base peak resulting from the loss of a propyl group from the butyryl side-chain

Electron-Induced (EI) Mass Fragmentation is Directed by Intramolecular H-Bonding in Two Isomeric Benzodipyran Systems

Abstract: The striking differences observed in the electron-induced (EI) mass fragmentation pathways of two isomeric benzodipyrans are attributable to hydrogen bonding in these molecules. In the "angular " isomer, 6-butyryl-5-hydroxy-2,2,8,8-tetramethyl-3,4,9,10-tetrahydro-2H,8H-benzo[1,2-b:3,4-b 1]dipyran (2), H-bonding occurs between the aromatic OH group and the alpha carbonyl moiety contained in the ortho-phenone group, whereas in the "linear " isomer, 10-butyryl-5-hydroxy-2,2,8,8-tetramethyl-3,4,6,7-tetrahydro-2H,8H-benzo-[1,2-b:5,4-b 1]dipyran (3), the aromatic OH group is para to the phenone moiety, effectively precluding any H-bonding. Semi-empirical molecular orbital calculations (AM1) were used to compare predicted sites of ionization with associated fragmentation patterns. In both molecules, the highest occupied molecular orbital (HOMO) was located predominantly on the aromatic moiety. Similarly, in the radical cation species of both compounds, maximum spin density was located over the aromatic rings. Neither the HOMO nor the spin density maps provided a rational explanation for the differences in fragmentation patterns of the two benzodipyran isomers. The H-bonding favors EI alpha aromatic ring C-O bond cleavage in the "angular " benzodipyran and in 5,7-dihydroxy-2,2-dimethyl-8-butyryl chroman (1), a relate

Mitochondrial ultrastructure and density in a primate model of persistent tardive dyskinesia

The use of neuroleptic drugs to treat schizophrenia is almost invariably associated with extrapyramidal movement disorders. One of these disorders, tardive dyskinesia (TD), can persist long after neuroleptic withdrawal suggesting that permanent neurological damage is produced. However, there appears to be no convincing pathology of TD and its pathogenesis remains unknown. Findings that neuroleptics interfere with normal mitochondrial function and produce mitochondrial ultrastructural changes in the basal ganglia of patients and animals suggest that mitochondrial dysfunction plays a role in TD. We have established a model for persistent TD in baboons that appears to involve compromised mitochondrial function. In this study, we evaluated two animals treated for 41 weeks with a derivative of haloperidol and two treated with vehicle only. Treatment was then withdrawn and the animals observed for a further 17-18 weeks. Treated animals developed abnormal orofacial signs that were consistent with TD. These symptoms persisted during the drug-free period. The animals were euthanased, the brains perfused-fixed then post-fixed in 4% paraformaldehyde and the caudate and putamen prepared for electron microscopy. Regardless of whether mitochondria were located in neural soma, excitatory terminals, gila or in non-somal neuropil there was no consistent difference either in size or number between treated and control animals. Thus, even if mitochondria in striatal neurons undergo ultrastructural alterations during neuroleptic therapy, these changes do not persist after drug withdrawal

Triquinane scaffolds: Shape and geometry as a function of saturation and bridgehead groups

Polycyclic hydrocarbon compounds, also known as ''cage compounds'', are of interest in drug discovery due to their versatility as scaffolds. Derivatives of both pentacycloundecane-dione and triquinane-dione have been the focus of numerous investigations as multifunctional neuroprotective drugs where these compounds were used as novel drug scaffolds with the ability to cross the blood brain barrier. Here we present the synthesis, characterization and single crystal X-ray analysis for two triquinane synthons; tricyclo[6.3.0.02,6]undecane-4,9-diene-3,11-dione (compound 5 crystallizes in the monoclinic system, unit cell parameters are: a = 6.5876 (12) A, b = 10.4204 (19) A, c = 12.074 (2) A; V = 825.4 (3) A3 and Z = 4) and tricyclo[6.3.0.02,6]undecane-3,11-dione (compound 6 crystallizes in monoclinic system, unit cell parameters are: a = 7.5992 (7) A, b = 10.7294 (10) A, c = 10.8664 (10) A; V = 884.04 (14) A3 and Z = 4); as well as a triquinane derivative, N-(3-methoxybenzyl)-3,11-azatricyclo[6.3.0.02,6]undecane (compound 11 crystallizes in triclinic system, unit cell parameters are: a = 7.6714 (7) A, b = 9.0100 (9) A, c = 11.2539 (11) A; V = 745.78 (12) A3 and Z = 2). The size and geometrical conformation of the triquinane scaffolds were compared to tetra and pentacycloundecanes, revealing that tricyclo[6.3.0.02,6]- undecane-3,11-dione experiences strain relief resulting in greater flexibility, a more asymmetric molecular shape and larger surface area. However, with the introduction of the aza-bridge in N-(3- methoxybenzyl)-3,11-azatricyclo[6.3.0.02,6]undecane, much of the flexibility and asymmetry is lost again. We also discuss the rearrangement mechanism for the observed retro cycloaddition and reversion, 0022-2860/$IS