@article {Patel1658, author = {S Patel and S Patel and R Marwood and F Emms and D Marston and P D Leeson and N R Curtis and J J Kulagowski and S B Freedman}, title = {Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.}, volume = {50}, number = {6}, pages = {1658--1664}, year = {1996}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {We identified a novel azaindole derivative, L-750,667, that has high affinity (Ki = 0.51 nM) and \>2000-fold selectivity for D4 dopamine receptors compared with its activity at D2 and D3 dopamine receptors. L-750,667 had little affinity for rat D1/D5 dopamine receptors, sigma binding sites, or 5-hydroxytryptamine1A or 5-hydroxytryptamine2 receptors. In functional studies, L-750,667 exhibited high affinity antagonist activity at D4 receptors, reversing dopamine (1 microM)-induced inhibition of cAMP accumulation in human embryonic kidney (HEK) cells expressing the human D4 receptor (hD4 HEK) with an EC50 value of 80 nM. The radioiodinated form of L-750,667 bound specifically to the human dopamine D4 receptor expressed in HEK cells and saturation analysis revealed a single high affinity binding site for [125I]L-750,667 (Kd = 0.16 +/- 0.06 nM). The maximum number of binding sites (Bmax) estimated using [125I]L-750,667 in hD4 HEK cells was 251 +/- 71 fmol/mg, which correlated well with the Bmax value determined using [3H]spiperone (227 +/- 83 fmol/mg) in the same membrane preparations. The pharmacological profile of [125I]L-750,667 binding to hD4 HEK cells was evaluated using known dopamine receptor agonists and antagonists. The rank order of potencies for dopamine receptor agonists was dopamine \> quinpirole \> 6,7-aminodihydroxytetralin \> 5,6-aminodihydroxytetralin. Dopamine receptor antagonists also showed high affinity, with a rank order of haloperidol \> chlorpromazine \> domperidone \> (+)-butaclamol \> (-)-sulpiride = (+)-sulpiride \> (+)-SCH23390 \> (-)-butaclamol. [125I]L-750,667, bound to D4 receptors in a stereoselective manner with (+)-butaclamol showing higher activity than its respective enantiomer (-)-butaclamol. These results show that [125I]L-750,667 is a novel, highly selective radioligand for dopamine D4 receptors and may be used to investigate the dopamine D4 receptor population in the central nervous system.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/50/6/1658}, eprint = {https://molpharm.aspetjournals.org/content/50/6/1658.full.pdf}, journal = {Molecular Pharmacology} }