Dopamine/serotonin receptor ligands. 9. Oxygen-containing midsized heterocyclic ring systems and nonrigidized analogues. A step toward dopamine D5 receptor selectivity.
Eleven-membered heterocycles (dibenz[g,j]-1-oxa-4-azacycloundecenes) and open-chain analogues were synthesized and investigated for affinities to human dopamine receptor subtypes. The moderately rigidized rings displayed nanomolar and subnanomolar Ki values at D1-like receptors with a significant D1 to D2 and a slight D5 to D1 selectivity. The open-chain analogues showed lower affinities but significant D1 to D2 selectivities. Compound 3 (Ki(D5) = 0.57 nmol) showed antagonistic or inverse agonistic binding characteristics in a functional Ca assay.
Wittig
Thomas W
TW
Institut für Pharmazie, Lehrstuhl für Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Decker
Michael
M
Lehmann
Jochen
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D010100:Oxygen; D011869:Radioligand Assay; D017447:Receptors, Dopamine D1 / Q000187:drug effects* / Q000378:metabolism; D050641:Receptors, Dopamine D5; D013329:Structure-Activity Relationship
C493605:DRD5 protein, human; D006574:Heterocyclic Compounds, 2-Ring; D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D017447:Receptors, Dopamine D1; D050641:Receptors, Dopamine D5; D010100:Oxygen; D002118:Calcium