Synthesis and pharmacological evaluation of thiazole and isothiazole derived apomorphines.
We have presented the synthesis of novel thiazolo- and isothiazolo-apomorphines 12-17 resulting-in part-from an unexpected isomerization step occurred during the acid-catalyzed rearrangement of precursor thiazolo-morphinandienes 3-5. These 2,3-disubstituted apomorphines represent a new group of A-ring substituted aporphines. The receptor binding studies revealed that with the exception of two derivatives all the tested compounds have limited affinity for dopamine-receptor subtypes. Functional calcium assay for the most active isothiazolo-apomorphine showed higher affinities for D(1) and D(2L) subtypes. The docking of these ligands has been modelled to human D(2) and D(3 )receptors. On the basis of the predicted models, we identified an important cation-p interaction for the binding of isothiazolo-apomorphine 16.
Sipos
Attila
A
Department of Organic Chemistry, University of Debrecen, Debrecen, Hungary. asipos@puma.unideb.hu
Mueller
Franziska K U
FK
Lehmann
Jochen
J
Berényi
Sándor
S
Antus
Sándor
S
D001058:Apomorphine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D003198:Computer Simulation; D017076:Computer-Aided Design; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007536:Isomerism; D008958:Models, Molecular; D015394:Molecular Structure; D011487:Protein Conformation; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists; D013844:Thiazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
C493593:DRD3 protein, human; D018491:Dopamine Agonists; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D013844:Thiazoles; C113776:dopamine D2L receptor; D001058:Apomorphine