Design and synthesis of photoaffinity-labeling ligands of the L-prolyl-L-leucylglycinamide binding site involved in the allosteric modulation of the dopamine receptor.
Pro-Leu-Gly-NH(2) (PLG), in addition to its endocrine effects, possesses the ability to modulate dopamine D(2) receptors within the central nervous system. However, the precise binding site of PLG is unknown. Potential photoaffinity-labeling ligands of the PLG binding site were designed as tools to be used in the identification of the macromolecule that possesses this binding site. Six different photoaffinity-labeling ligands were designed and synthesized on the basis of the gamma-lactam PLG peptidomimetic 1. The 4-azidobenzoyl and 4-azido-2-hydroxybenzoyl photoaffinity-labeling moieties were placed at opposite ends of PLG peptidomimetic 1 to generate a series of ligands that potentially could be used to map the PLG binding site. All of the compounds that were synthesized possessed activity comparable to or better than PLG in enhancing [(3)H]-N-propylnorapomorphine agonist binding to dopamine receptors. Photoaffinity ligands that were cross-linked to the receptor preparation produced a modulatory effect that was either comparable to or greater than the increase in agonist binding produced by the respective ligands that were not cross-linked to the dopamine receptor. The results indicate that these photoaffinity-labeling agents are binding at the same allosteric site as PLG and PLG peptidomimetic 1.
Fisher
Abigail
A
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St. SE, Minneapolis, Minnesota 55455-0343, USA.
Mann
Amandeep
A
Verma
Vaneeta
V
Thomas
Nancy
N
Mishra
Ram K
RK
Johnson
Rodney L
RL
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002417:Cattle; D015259:Dopamine Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D008024:Ligands; D009075:MSH Release-Inhibiting Hormone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D008968:Molecular Conformation; D019920:Photoaffinity Labels / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000187:drug effects*; D013329:Structure-Activity Relationship
D015259:Dopamine Agents; D008024:Ligands; D019920:Photoaffinity Labels; D017448:Receptors, Dopamine D2; D009075:MSH Release-Inhibiting Hormone; D001058:Apomorphine