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Molecular Pharmacology

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Abstract

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.

S Patel, S Patel, R Marwood, F Emms, D Marston, P D Leeson, N R Curtis, J J Kulagowski and S B Freedman
Molecular Pharmacology December 1996, 50 (6) 1658-1664;
S Patel
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S Patel
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R Marwood
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F Emms
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D Marston
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P D Leeson
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N R Curtis
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J J Kulagowski
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S B Freedman
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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.

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Molecular Pharmacology
Vol. 50, Issue 6
1 Dec 1996
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Abstract

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.

S Patel, S Patel, R Marwood, F Emms, D Marston, P D Leeson, N R Curtis, J J Kulagowski and S B Freedman
Molecular Pharmacology December 1, 1996, 50 (6) 1658-1664;

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Abstract

Identification and pharmacological characterization of [125I]L-750,667, a novel radioligand for the dopamine D4 receptor.

S Patel, S Patel, R Marwood, F Emms, D Marston, P D Leeson, N R Curtis, J J Kulagowski and S B Freedman
Molecular Pharmacology December 1, 1996, 50 (6) 1658-1664;
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