Fancy bioisosteres: metallocene-derived G-protein-coupled receptor ligands with subnanomolar binding affinity and novel selectivity profiles.
Metallocene-derived bioisosteres lead to exceptionally strong binding G-protein-coupled receptor ligands, indicating substantial plasticity of the receptor excluded volume. Novel binding profiles of ferrocenylcarboxamides combining subnanomolar Ki values for the dopamine D4 receptor (1a, 0.52 nM; 1b, 0.63 nM) with superpotent serotonin 5-hydroxytryptamine1A (1a, 0.50 nM) and dopamine D3 receptor binding (1b, 0.64 nM) and selective D4 agonist properties of the ruthenocene 1c may be a starting point for highly beneficial central nervous system active drugs.
Schlotter
Karin
K
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Boeckler
Frank
F
Hübner
Harald
H
Gmeiner
Peter
P
D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003517:Cyclopentanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008024:Ligands; D000075163:Metallocenes; D008938:Mitosis / Q000187:drug effects; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D050637:Receptors, Dopamine D3; D050638:Receptors, Dopamine D4; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D012428:Ruthenium; D013329:Structure-Activity Relationship
D003517:Cyclopentanes; D005296:Ferrous Compounds; D008024:Ligands; D000075163:Metallocenes; D009942:Organometallic Compounds; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D043562:Receptors, G-Protein-Coupled; C013108:metallocene; D044282:Receptor, Serotonin, 5-HT1A; C016721:ruthenocene; D050638:Receptors, Dopamine D4; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D012428:Ruthenium; C004998:ferrocene