ABSTRACT
The M4 mAChR is implicated in several CNS disorders and possesses an allosteric binding site for which ligands modulating the affinity and/or efficacy of ACh may be exploited for selective receptor targeting. We report the synthesis of a focused library of putative M4 PAMs derived from VU10004. These compounds investigate the pharmacological effects of target thieno[2,3-b]pyridines assembled from primary cycloalkanamines and cyclic secondary amines providing useful estimates of affinity (KB), cooperativity (αß), and direct agonist properties (τB).
Subject(s)
Cholinergic Agonists/chemical synthesis , Cholinergic Agonists/pharmacology , Receptor, Muscarinic M4/metabolism , Thienopyridines/chemical synthesis , Thienopyridines/pharmacology , Acetylcholine/metabolism , Allosteric Regulation , Allosteric Site/drug effects , Animals , CHO Cells , Cholinergic Agonists/chemistry , Cricetulus , Drug Evaluation , Humans , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Molecular Structure , Phosphorylation , Thienopyridines/chemistryABSTRACT
A series of different 1-monosubstituted and 1,1-disubstituted 1,2,3,4-tetrahydro-isoquinolines was synthesized in high yields from different ketoamides. We have developed a convenient method for the synthesis of disubstituted derivatives by interaction of ketoamides with organomagnesium compounds, followed by cyclization in the presence of catalytic amounts of p-toluenesulfonic acid (PTSA). A number of substituents at the C-1 in the isoquinoline skeleton were introduced varying either carboxylic acid or organomagnesium compound. Some of the obtained 1,1-dialkyl-1,2,3,4-tetrahydro-isoquinolines possess contractile activity against guinea pig's gastric smooth muscle preparations.
Subject(s)
Chemistry, Pharmaceutical/methods , Cholinergic Agonists , Muscle Contraction/drug effects , Muscle, Smooth/drug effects , Organometallic Compounds , Receptors, Cholinergic/metabolism , Tetrahydroisoquinolines , Acetylcholine/metabolism , Acetylcholine/pharmacology , Amides/chemistry , Animals , Area Under Curve , Benzenesulfonates/chemistry , Catalysis , Cholinergic Agonists/chemical synthesis , Cholinergic Agonists/pharmacology , Cyclization , Guinea Pigs , Magnetic Resonance Spectroscopy , Male , Muscle Contraction/physiology , Muscle, Smooth/physiology , Organ Culture Techniques , Organometallic Compounds/chemical synthesis , Organometallic Compounds/pharmacology , Structure-Activity Relationship , Tetrahydroisoquinolines/chemical synthesis , Tetrahydroisoquinolines/pharmacologyABSTRACT
A fully automated and GMP compatible synthesis has been developed to reliably label the M1 receptor agonist GSK1034702 with carbon-11. Stille reaction of the trimethylstannyl precursor with [¹¹C]methyl iodide afforded [¹¹C]GSK1034702 in an estimated 10 ± 3% decay corrected yield. This method utilises the commercially available modular laboratory equipment and provides high purity [¹¹C]GSK1034702 in a formulation suitable for human use.
Subject(s)
Benzimidazoles/chemical synthesis , Cholinergic Agonists/chemical synthesis , Radiopharmaceuticals/chemical synthesis , Receptor, Muscarinic M1/agonists , Automation, Laboratory , Carbon Radioisotopes , Isotope LabelingABSTRACT
We report the synthesis and pharmacological properties of several cytisine derivatives. Among them, two 10-substituted derivatives showed much higher selectivities for the alpha4beta2 nAChR subtype in binding assays than cytisine. The 9-vinyl derivative was found to have a very similar agonist activity profile to that of cytisine.
Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Nicotine/chemistry , Nicotine/pharmacology , Alkaloids/chemical synthesis , Azocines/chemical synthesis , Azocines/chemistry , Azocines/pharmacology , Cholinergic Agonists/chemical synthesis , Cholinergic Agonists/chemistry , Cholinergic Agonists/pharmacology , Hydrophobic and Hydrophilic Interactions , Ligands , Molecular Structure , Nicotine/chemical synthesis , Nicotine/classification , Quinolizines/chemical synthesis , Quinolizines/chemistry , Quinolizines/pharmacology , Receptors, Cholinergic/metabolismABSTRACT
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
A series of conformationally restricted analogues of nicotine has been synthesized and evaluated as agonists of neuronal acetylcholine receptors. Compound 2 (SIB-1663), which selectively activated human recombinant alpha 2 beta 4 and alpha 4 beta 4 nAChRs, was shown to be active in animal models of Parkinson's disease and pain.