ABSTRACT
The Asia Pacific Observatory on Health Systems and Policies (the APO) is a collaborative partnership of interested governments, international agencies, foundations, and researchers that promotes evidence-informed health systems policy regionally and in all countries in the Asia Pacific region. The APO collaboratively identifies priority health system issues across the Asia Pacific region; develops and synthesizes relevant research to support and inform countries' evidence-based policy development; and builds country and regional health systems research and evidence-informed policy capacity.
Subject(s)
Health Care Sector , Health Systems PlansABSTRACT
Cyproheptadine is a drug that shows high affinity for type 2 (5-HT2) receptors. We studied a series of compounds obtained by modification of the tricyclic system of Cyp (dibenzocycloheptadiene): 2f (thioxanthene), 2g (xanthene), 2h (dihydrodibenzocycloheptadiene), 2j (diphenyl), 2i (fluorene), and 3b (phenylmethyl). Their activities at the rat cerebral cortex 5-HT2A receptor were (pKi +/- S.E.M.): 8.80 +/- 0.11 (Cyp), 8.60 +/- 0.07 (2f), 8.40 +/- 0.02 (2g), 8.05 +/- 0.03 (2h), 7.87 +/- 0.12 (2j), 6.70 +/- 0.02 (2i) and 6.45 +/- 0.02 (3b); those at the rat stomach fundus 5-HT2B receptor (pA2 +/- S.E.M.) were: 9.14 +/- 0.25 (Cyp), 8.49 +/- 0.07 (2f), 7.58 +/- 0.58 (2g), 7.02 +/- 0.14 (2h), 6.07 +/- 0.20 (2j), and undetectable (2i, 3b): and those at the pig choroidal plexus 5-HT2C receptor (pKi +/- S.E.M.) were: 8.71 +/- 0.08 (Cyp), 8.68 +/- 0.01 (2f), 8.58 +/- 0.20 (2g), 7.95 +/- 0.05 (2h), 7.57 +/- 0.04 (2j), 6.98 +/- 0.04 (2i) and 6.63 +/- 0.20 (3b). The slopes did not differ significantly from unity. The compounds exhibited the same order of activities at every type of receptor, and the most active molecules presented certain steric (butterfly conformation of the tricyclic system) and electrostatic (proton affinity on the top of the central rings) patterns. It is concluded that the activity of cyproheptadine derivatives at 5-HT2 receptors is related to these molecular features, which make feasible a common disposition to interact with all three 5-HT2 subtypes.
Subject(s)
Cyproheptadine/analogs & derivatives , Cyproheptadine/chemical synthesis , Receptors, Serotonin/drug effects , Serotonin Antagonists/chemical synthesis , Animals , Binding, Competitive/drug effects , Cerebral Cortex/metabolism , Choroid Plexus/drug effects , Choroid Plexus/metabolism , Cyproheptadine/pharmacology , Ergolines/metabolism , Gastric Fundus/drug effects , In Vitro Techniques , Ketanserin/metabolism , Kinetics , Male , Models, Molecular , Rats , Rats, Sprague-Dawley , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , SwineABSTRACT
The formulation of HIV-1 PR inhibitors as anti-viral drugs has been hindered by the appearance of protease strains that present drug resistance to these compounds. The mechanism by which the HIV-1 PR mutants lower their affinity for the inhibitor is not yet fully understood. We have applied a modified Poisson-Boltzmann method to the evaluation of the molecular interactions that contribute to the lowering of the inhibitor affinity to some polar mutants at position 82. These strains present drug resistance behavior and hence are ideally suited for these studies. Our results indicate that the reduction in binding affinity is due to the solvation effects that penalize the binding to the more polar mutants. The inhibitor binding ranking of the different mutants can be explained from the analysis of the different components of our free energy scoring function.
Subject(s)
HIV Protease Inhibitors/chemistry , HIV Protease Inhibitors/metabolism , HIV Protease/chemistry , HIV Protease/metabolism , Arginine , Binding Sites , Glutamic Acid , HIV-1/enzymology , Kinetics , Mutagenesis, Site-Directed , Point Mutation , Recombinant Proteins/chemistry , Recombinant Proteins/metabolism , Solutions , ThermodynamicsABSTRACT
We have developed a simple approach for the evaluation of the free energies of inhibitor binding to the protease of the human immunodeficiency virus (HIV-1 PR). Our algorithm is based on the observation that most groups that line the binding pockets of this enzyme are hydrophobic in nature. Based on this fact, we have likened the binding of an inhibitor to this enzyme to its transfer from water to a medium of lower polarity. The resulting expression produced values for the free energy of binding of inhibitors to the HIV-1 PR that are in good agreement with experimental values. The additive nature of this approach has enabled us to partition the free energy of binding into the contributions of single fragments. The resulting analysis clearly indicates the existence of a ranking in the participation of the enzyme's subsites in binding. Although all the enzyme's pockets contribute to binding, the ones that bind the P2-P'2 span of the inhibitor are in general the most critical for high inhibitor potency. Moreover, our method has allowed us to determine the nature of the functional groups that fit into given enzyme binding pockets. Perusal of the energy contributions of single side chains has shown that a large number of hydrophobic and aromatic groups located in the central portion of the HIV-1 PR inhibitors present optimal binding. All of these observations are in agreement with experimental evidence, providing a validation for the physical relevancy of our model.
Subject(s)
HIV Protease Inhibitors/metabolism , HIV Protease/metabolism , Solvents , Binding Sites , HIV Protease/chemistry , Molecular Structure , ThermodynamicsABSTRACT
Kaempferol 3-O-[alpha-L-rhamnopyranosyl (1-->6)-beta-D-glucopyranoside] and kaempferol 3-O-[beta-D-glucopyranoside] were isolated from the leaves of Hedyosmum bonplandianum H.B.K. (Chloranthaceae), which is used in Colombian folk medicine as an analgesic. The n-butanol extract and the glycosyl flavonoids isolated exhibited significant analgesic activity in mice.
Subject(s)
Analgesics/pharmacology , Flavonoids/pharmacology , Glycosides/pharmacology , Plants, Medicinal/chemistry , Analgesics/chemistry , Analgesics/isolation & purification , Animals , Carbohydrate Sequence , Flavonoids/chemistry , Flavonoids/isolation & purification , Glycosides/chemistry , Glycosides/isolation & purification , Male , Mice , Molecular Sequence Data , Molecular Structure , Rats , Rats, WistarABSTRACT
Eight lignans (+/-)-syringaresinol, (-)-pinoresinol, (+)-sesamin, (+)-eudesmin, (+)-epieudesmin, (-)-asarinin, (-)-matairesinol, (-)-kobusin, two terpenes lupeol, beta-sitosterol, one aliphatic unsaturated amide, hydroxy-gamma-sanshoöl, and one alkaloid, magnoflorine, were isolated from ZANTHOXYLUM species of Central and South America. Their structures were elucidated mainly by (1)H-, (13)C-NMR, and mass spectroscopy.
