ABSTRACT
Two series of compounds, 2 and 3, were synthesized and their binding affinities were evaluated for the human recombinant muscarinic M(1) receptor subtype expressed in CHO cells. Comparing their binding affinities for the NMS binding sites and the Oxo-M binding sites, they were assumed as agonists. In particular, compound 2e was a good ligand for the agonist binding sites with an IC(50) of 23 nM, which represents over 1585 times stronger binding than for the antagonist binding sites.
Subject(s)
Aza Compounds/chemical synthesis , Aza Compounds/metabolism , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/metabolism , Receptors, Muscarinic/metabolism , Animals , CHO Cells , Cricetinae , Ligands , Receptor, Muscarinic M1Subject(s)
Cephalosporins/chemical synthesis , Coumarins/isolation & purification , Triazoles/chemical synthesis , Cephalosporins/pharmacology , Coumarins/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Structure-Activity Relationship , Triazoles/pharmacologyABSTRACT
A series of 3-(3-phenylisoxazol-5-yl)methylidene-1-azabicycles synthesized showed different binding characteristics to acetylcholine receptors depending on the substituents on the phenyl ring. Small polar substituents gave preferential binding affinity to nicotinic receptors, and large hydrophobic substituents to muscarinic receptors.
Subject(s)
Aza Compounds/chemistry , Bridged Bicyclo Compounds, Heterocyclic/chemistry , Isoxazoles/chemistry , Receptors, Cholinergic/chemistry , Alkaloids/chemistry , Azocines , Binding, Competitive , Molecular Structure , N-Methylscopolamine/chemistry , Protein Binding , Quinolizines , Receptors, Muscarinic/chemistry , Receptors, Nicotinic/chemistryABSTRACT
Three-dimensional QSAR studies for two series of new oxazolidinone antibacterial agents were conducted using the comparative molecular field analysis (CoMFA). In vitro activities (MICs) of the compounds against methicillin-resistant Staphylococcus aureus 88 (MRSA 88) exhibited a strong correlation with their steric, electrostatic factors and lipophilicities.
Subject(s)
Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Two series of oxazolidinone derivatives having substituted isoxazoles were synthesized and tested for antibacterial activities against several Gram-positive strains including the resistant strains of Staphylococcus and Enterococcus, such as MRSA, CRSA, MSSA and VRE. Some of them showed in vitro activities (MIC) comparable or superior to the reference compound vancomycin.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Isoxazoles/chemistry , Oxazoles/chemical synthesis , Oxazoles/pharmacology , Anti-Bacterial Agents/chemistry , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Oxazoles/chemistryABSTRACT
The synthesis and in vitro synergies of 2 beta-alkenyl and oxyiminopenam sulfone derivatives are described. Most of the compounds synthesized exhibited good inhibitory activities and synergistic antibacterial activities with piperacillin and ceftriaxone, respectively, against several beta-lactamase producing strains. Particularly the 2 beta-alkenylpenam sulfone derivatives. 1e and 1g, showed good synergistic activity with ceftriaxone against Citrobacter freundi NIH 10018-68 and Proteus vulgaris 20. Also the compounds 2a, 2c, and 2f, 2 beta-oxyiminopenam sulfone derivatives, exhibited improved synergistic activity with piperacillin against Citrobacter freundi NIH 10018-68.
Subject(s)
Enzyme Inhibitors/chemical synthesis , Penicillanic Acid/analogs & derivatives , Penicillanic Acid/chemical synthesis , Sulfones/chemical synthesis , beta-Lactamase Inhibitors , Ceftriaxone/pharmacology , Cephalosporins/pharmacology , Citrobacter freundii/drug effects , Drug Synergism , Enzyme Inhibitors/pharmacology , Microbial Sensitivity Tests , Penicillanic Acid/pharmacology , Penicillins/pharmacology , Piperacillin/pharmacology , Sulfones/pharmacologyABSTRACT
Some noncompetitive inhibitors (e.g., ganglionic blockers) exhibit selectivity for the inhibition of neuronal nicotinic acetylcholine receptors (nAChRs). This study characterizes the mechanism of selective long-term inhibition of neuronal and muscle-neuronal chimeric nAChRs by bis(2,2,6,6-tetramethyl-4-piperidinyl) sebacate (bis-TMP-10 or BTMPS), a bifunctional form of the potent ganglionic blocker tetramethylpiperidine. Long-term inhibition of neuronal nAChRs by bis-TMP-10 has been previously demonstrated to arise, at least in part, from the binding of the bis compound to neuronal beta-subunits. In this study, long-term inhibition is demonstrated to be dependent upon the presence of sequence element(s) within the pore-lining second transmembrane domain (tm2) of neuronal beta-subunits; however, the inhibitor binding site itself does not appear to be contained within the segment of the channel pore influenced by the membrane electric field. Specifically, our results imply that bis-TMP-10 interacts with an activation-sensitive element, the availability of which may be regulated by a sequence in the tm2 domain. Furthermore, we demonstrate a compound length requirement for long-term inhibition that would be consistent with binding to multiple sites located on the extracellular portion of the receptor.
