ABSTRACT
A number of novel pyrazolomorphinans have been synthesized in excellent yields by the reaction of the enolic morphinan diketones 6 with various hydrazines. Hydrazine dihydrochloride led to the N-unsubstituted tautomeric pyrazoles 7a in equilibrium with 9a and 8a in equilibrium with 10a which could not be separated. Arylhydrazines on the other hand furnished the regioisomeric pyrazolomorphinans 7 and 9 as well as 8 and 10, which could be isolated and characterized. The structures of the new compounds were clarified by their spectra, the assignment of the regioisomeres was achieved by determination of NOE enhancements. Compounds 6a, 7c, 8b and 10c have been evaluated for their affinity at mu and kappa opioid receptors in radioligand binding assays. Their ability to inhibit [3H] DAMGO binding to mu and [3H] U 69,593 binding to kappa opioid receptors has been found to be comparable with that of codeine.
Subject(s)
Morphinans/chemical synthesis , Receptors, Opioid, kappa/drug effects , Receptors, Opioid, mu/drug effects , Animals , Cattle , In Vitro Techniques , Ligands , Magnetic Resonance Spectroscopy , Morphinans/pharmacologyABSTRACT
A number of novel pyridazinomorphinans have been synthesized by the inverse electron demand Diels-Alder reaction of various 3,6-disubstituted 1,2,4,5-tetrazines with enamines derived from dihydrocodeinone and with codeinone. Reduction of some of the pyridazinomorphinans did not furnish the expected pyrroloepoxymorphinans; in all cases investigated reductive cleavage of the epoxybridge was observed to yield dihydropyridazino- or pyrrolomorphinans. The structures of all new compounds were assigned by the spectral data, that of the cycloadduct of codeinone was additionally verified by X-ray crystallography. Compounds 5a, 8, 11a and 16 have been evaluated for their affinity at mu and kappa opioid receptors in radioligand binding assays. Their ability to inhibit [3H]DAMGO binding at mu and [3H]U 69.593 binding at kappa receptors, respectively as compared to codeine has been found to be lower.
Subject(s)
Benzeneacetamides , Morphinans/chemical synthesis , Pyrazines/chemical synthesis , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Animals , Binding, Competitive , Cattle , Cell Membrane/metabolism , Corpus Striatum/metabolism , Crystallography, X-Ray , Enkephalin, Ala(2)-MePhe(4)-Gly(5)- , Enkephalins/metabolism , Indicators and Reagents , Models, Molecular , Molecular Structure , Morphinans/chemistry , Morphinans/pharmacology , Pyrazines/chemistry , Pyrazines/pharmacology , Pyrrolidines/metabolism , Radioligand Assay , Receptors, Opioid, kappa/agonists , Receptors, Opioid, mu/agonistsABSTRACT
Three different soil types (two sandy materials and one till soil type) were sterilized with 14 different sterilization methods or variations. The cation-exchange capacity and specific surface of the soil samples were chosen as control parameters of physico-chemical modifications in the soils. Incubation of soil samples in the presence of Na-azide and HgCl2, in addition to tyndallization and fractionated heating of soil lead to a significant reduction of microorganisms. UV radiation and alternating freezing and thawing of soil had no influence on the number of microorganisms. The application of mercury-II-chloride did not lead to the expected sterilization, especially with till. A sterilization of soil is possible by using formaldehyde and ethylene oxide gassing, in addition to autoclaving and gamma radiation. No microorganisms could be detected in the soils after application of these sterilization methods. The cation exchange capacity of the soils was only slightly influenced with these methods. The use of gamma radiation seems to be the best method for sterilization of soils.
