title: Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding.
abstract: Phenylazocarboxamides can serve as bioisosteres for cinnamides, which are widely occurring substructures in medicinal chemistry. Starting from our lead compound 2, the introduction of additional fluoro substituents and the exchange of the methoxyphenylpiperazine head group by an aminoindane moiety was investigated resulting in dopamine D3 receptor antagonists and agonists with Ki values in the sub- and low-nanomolar range. As a potentially irreversible ligand, the 3,4,5-trifluoro-substituted phenylazocarboxamide 7 was investigated for its N-arylating properties by incubation with the protected lysine analog 18 and with the L89K mutant of the dopamine D3 receptor. Whereas covalent bond formation with the lysine unit in TM2 of D3 could not be detected, substantial N-arylation of the side chain of the model compound 18 has been observed.
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Amelie L
authors.initials: AL
authors.lastname: Bartuschat
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Tamara
authors.initials: T
authors.lastname: Schellhorn
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Schuhstraße 19, 91052 Erlangen, Germany. Electronic address: markus.heinrich@fau.de.
authors.forename: Markus R
authors.initials: MR
authors.lastname: Heinrich
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000737:chemistry; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005461:Fluorine / Q000737:chemistry; D018698:Glutamic Acid / Q000737:chemistry; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D015394:Molecular Structure; D009154:Mutation; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D008024:Ligands; D050637:Receptors, Dopamine D3; D005461:Fluorine; D018698:Glutamic Acid; D008239:Lysine
keywords: Azocarboxamide; Bioisosteres; Covalent ligands; D(3) receptor; Dopamine; GPCR