1,1'-Disubstituted ferrocenes as molecular hinges in mono- and bivalent dopamine receptor ligands.
On the basis of previous work on dopaminergic partial agonists of type 1 and 2, disubstituted ferrocenes are presented as valuable arene bioisosteres. Because substituents at the distal cyclopentadienyl ring are able to adjust the relative disposition that is required for ligand binding, disubstituted ferrocenes can act as molecular hinges. Taking advantage of click chemistry, the regioselective construction and functionalization of the target molecules is reported. Thus triazole derived appendages were used for the fine-tuning of biological activity and for the attachment of linker units generating bivalent GPCR ligands. Receptor binding was evaluated by radioligand displacement experiments, revealing superaffinity with sub- to single-digit nanomolar K(i) values for particular test compounds. As a neutral antagonist at the dopamine receptors D3 and D4 and a potent partial agonist at the D2 subtype (intrinsic activity = 57%, EC(50) = 2.5 nM), the bifunctional ferrocene 10b revealed a novel and unique activity profile.
Huber
Daniela
D
Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, 91052 Erlangen, Germany.
Hübner
Harald
H
Gmeiner
Peter
P
D000818:Animals; D016466:CHO Cells; D003342:Corpus Striatum / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D018491:Dopamine Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D054333:Drug Partial Agonism; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D000075163:Metallocenes; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
C545546:1'-(1-benzyl-1H-1,2,3-triazole-4-yl)-N-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)ferrocene-1-carboxamide; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D005296:Ferrous Compounds; D008024:Ligands; D000075163:Metallocenes; D011954:Receptors, Dopamine; C004998:ferrocene