ABSTRACT
The potential toxicological liabilities of the M(2) muscarinic antagonist 1 were addressed by replacing the methylenedioxyphenyl moiety with a p-methoxyphenyl group, resulting in M(2) selective compounds such as 3. Several halogenated naphthamide derivatives of 3 were studied in order to improve the pharmacokinetic profile via blockage of oxidative metabolism. Compound 4 demonstrated excellent M(2) affinity and selectivity, human microsomal stability, and oral bioavailability in rodents and primates.
Subject(s)
Benzylidene Compounds/chemistry , Dioxoles/chemistry , Dioxoles/pharmacology , Muscarinic Antagonists/chemistry , Muscarinic Antagonists/pharmacology , Receptors, Muscarinic/drug effects , Sulfones/chemistry , Sulfones/pharmacology , Acetylcholine/analysis , Acetylcholine/metabolism , Administration, Oral , Animals , Area Under Curve , Benzylidene Compounds/metabolism , Cytochrome P-450 Enzyme System/metabolism , Drug Design , Drug Evaluation, Preclinical , Drug Stability , Humans , Macaca fascicularis , Microdialysis , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Muscarinic Antagonists/blood , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
Benzylidene ketal derivatives were investigated as selective M2 receptor antagonists for the treatment of Alzheimer's disease. Compound 10 was discovered to have subnanomolar M2 receptor affinity and 100-fold selectivity against other muscarinic receptors. Also, 10 demonstrated in vivo efficacy in rodent models of muscarinic activity and cognition.
Subject(s)
Benzylidene Compounds/metabolism , Benzylidene Compounds/pharmacokinetics , Receptors, Muscarinic/metabolism , Acetylcholine/metabolism , Alzheimer Disease/drug therapy , Animals , Benzylidene Compounds/chemical synthesis , Brain/metabolism , Cholinergic Agonists/chemical synthesis , Cholinergic Agonists/metabolism , Cholinergic Agonists/pharmacokinetics , Cognition/drug effects , Drug Stability , Humans , Memory/drug effects , Muscarinic Antagonists/chemical synthesis , Muscarinic Antagonists/metabolism , Muscarinic Antagonists/pharmacokinetics , Protein Binding , Rats , Receptor, Muscarinic M2 , Structure-Activity RelationshipABSTRACT
The white rot fungi Lentinula edodes, Phanerochaete chrysosporium, Pleurotus sajor-caju, Flammulina velutipes, and Schizophyllum commune were grown in liquid media containing C-lignin-labelled wood, and the formation of water-soluble C-labelled products and CO(2), the growth of the fungi, and the activities of extracellular lignin peroxidase, manganese peroxidase, and laccase were measured. Conditions that affect the rate of lignin degradation were imposed, and both long-term (0- to 16-day) and short-term (0- to 72-h) effects on the production of the two types of product and on the activities of the enzymes were monitored. The production of CO(2)-labelled products from the aqueous ones was also investigated. The short-term studies showed that the different conditions had different effects on the production of the two products and on the activities of the enzymes. Nitrogen sources inhibited the production of both products by all species when differences in growth could be discounted. Medium pH and manganese affected lignin degradation by the different species differently. With P. chrysosporium, the results were consistent, with lignin peroxidase playing a role in lignin solubilization and manganese peroxidase being important in subsequent CO(2) production.
ABSTRACT
Two bacterial isolates from the intertidal zone produced significant quantities of extracellular polysaccharide with interesting properties. One polysaccharide was named PS 3a24; the other was named PS 3a35. The relative proportion of sugars in PS 3a35 was 51.6% glucose, 39.0% galactose, 3.1% mannose, and 6.3% rhamnose, with a trace of an unidentified sugar. PS 3a24 was composed of 40.2% glucose, 57.2% galactose, and 2.6% mannose. PS 3a35 contained 6% pyruvate, whereas PS 3a24 contained no pyruvate. Both exhibited high specific viscosity, pseudoplasticity, and stability over a wide range of pH in the presence of a variety of salts. The viscosity of PS 3a35 was relatively insensitive to increasing temperature, whereas that of PS 3a24 showed an irreversible drop on heating.
ABSTRACT
Earlier studies indicated that bacteria responsible for nitrogenase activity of some grasses are located inside the roots. Those studies were conducted with excised roots in which a long, unexplained "lag phase" occurred before initiation of nitrogenase activity. When hydroponically maintained Spartina alterniflora Loisel. was incubated in a two-compartment system with acetylene, ethylene was produced following, at most, a 2-hour lag in both the upper (shoot) and lower (roots + water) phases. Ethylene production in the upper phase not attributable to leaf-associated acetylene-reducing activity or to diffusion of ethylene from around the roots is considered to represent "endorhizal acetylene-reducing activity," the internally produced ethylene diffusing into the upper phase via the lacunae. Ethylene produced in the lower phase is designated "exorhizal acetylene-reducing activity." The endorhizal acetylene-reducing activity, in comparison to exorhizal activity, was relatively insensitive to additions of HgCl(2), NH(4)Cl, or carbon sources to the lower phase. Post-lag acetylene-reducing activity of roots excised from plants growing in soil responded to additions in a manner similar to that of endorhizal acetylene-reducing activity, whereas post-lag acetylene-reducing activity of rhizosphere soil responded in a manner similar to that of exorhizal acetylene-reducing activity.
