Switching and Conformational Fixation of Amides Through Proximate Positive Charges.

Tertiary amides, which usually occur as cis/trans mixtures, can be effectively shifted to the cis conformation by placing a positive charge in close proximity to the amide carbonyl. This effect was used to prepare cis-configured prolyl amides and to facilitate a strongly rotamer-dependent radical cyclization.

Fluoro-substituted phenylazocarboxamides: Dopaminergic behavior and N-arylating properties for irreversible binding.

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.

Synthesis and evaluation of fluoro substituted pyridinylcarboxamides and their phenylazo analogues for potential dopamine D3 receptor PET imaging.

A series of fluoro substituted pyridinylcarboxamides and their phenylazo analogues with high affinity and selectivity for the dopamine D3 receptor was synthesized by the use of 6-fluoropyridine-3-carbonyl chloride (1) and fluorophenylazocarboxylic ester (2). Several of these compounds (9a-e and 10a-h) have been evaluated in vitro, among which 9b, 10a, 10c and 10d proved to have at least single-digit nanomolar affinity for D3. They also exhibit considerable selectivity over the other dopamine receptor subtypes and noteworthy selectivity over the structurally related serotonin receptor subtypes 5-HT(1A) and 5-HT₂, offering potential radiotracers for positron emission tomography.

Fast and efficient (18) F-labeling by [(18) f]fluorophenylazocarboxylic esters.

Introduction of [(18) F]fluoride ion into the aromatic core of phenylazocarboxylic esters was achieved in only 30 seconds, with radiochemical yields of up to 95 % (85(±10) %). For labeling purposes, the resulting (18) F-substituted azoester can be further converted in radical-arylation reactions to give biaryls, or in substitutions at its carbonyl unit to produce azocarboxamides.