Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the binding and activity at muscarinic receptor subtypes and chimeras.
As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M(2) for 13d and M(4) for 1) and enhance functional efficacy at M(4) receptors for 13e and 18b. Moreover, compound 1 exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.
Tejada
Frederick R
FR
Department of Medicinal and Biological Chemistry, The University of Toledo, 2801 W. Bancroft St., Toledo, Ohio 43606, USA.
Nagy
Peter I
PI
Xu
Min
M
Wu
Cindy
C
Katz
Tricia
T
Dorsey
Jason
J
Rieman
Melissa
M
Lawlor
Elizabeth
E
Warrier
Manya
M
Messer
William S
WS
D000818:Animals; D014150:Antipsychotic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D000242:Cyclic AMP / Q000096:biosynthesis; D015195:Drug Design; D006801:Humans; D006868:Hydrolysis; D008024:Ligands; D051379:Mice; D008958:Models, Molecular; D018721:Muscarinic Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010716:Phosphatidylinositols / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D014150:Antipsychotic Agents; D008024:Ligands; D018721:Muscarinic Agonists; D010716:Phosphatidylinositols; D010880:Piperidines; D011976:Receptors, Muscarinic; D011993:Recombinant Fusion Proteins; D013830:Thiadiazoles; C517244:tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) (3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl) ether; D000242:Cyclic AMP