Design, synthesis, and pharmacological characterization of 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]- 2-iodobenzonitrile as a high-affinity nonsteroidal androgen receptor ligand.
4-[4, 4-Dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-+ ++trif luoromethylbenzonitrile (RU 59063) is a prototype of a new class of high-affinity nonsteroidal androgen receptor (AR) ligands. The search for a radioiodinated AR ligand prompted us to synthesize 4-[4, 4-dimethyl-3-(4-hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl]-2-i odo benzonitrile (DTIB) wherein the trifluoromethyl group of RU 59063 was substituted with the similarly hydrophobic iodine atom. DTIB displayed subnanomolar binding affinity (K(i) = 0.71 +/- 0.22 nM) for the rat AR in competitive binding assays. Additionally, DTIB demonstrated potent agonist activity, comparable to that of the natural androgen 5alpha-dihydrotestosterone (DHT), in a cell-based functional assay (cotransfection assay). DTIB represents a new lead for the development of high-affinity radioiodinated AR radioligands.
Van Dort
M E
ME
Division of Nuclear Medicine, Department of Internal Medicine and Department of Human Genetics, The University of Michigan Medical School, Ann Arbor, Michigan 48109-0552, USA. mvandort@umich.edu
Robins
D M
DM
Wayburn
B
B
D000728:Androgens; D000818:Animals; D001667:Binding, Competitive; D002460:Cell Line; D013196:Dihydrotestosterone / Q000494:pharmacology; D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D009570:Nitriles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011467:Prostate / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D011944:Receptors, Androgen / Q000378:metabolism* / Q000502:physiology; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015533:Transcriptional Activation
C413353:4-(4,4-dimethyl-3-(4--hydroxybutyl)-5-oxo-2-thioxo-1-imidazolidinyl)-2-iodobenzonitrile; D000728:Androgens; D007093:Imidazoles; D008024:Ligands; D009570:Nitriles; D011944:Receptors, Androgen; D013871:Thiones; D013196:Dihydrotestosterone; C086459:RU 59063