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SCH 23390—The first selective dopamine D-1 antagonist
European Journal of Pharmacology, 91 (1983) 153-154 Elsevier
153
Rapid communication SCH 23390 - THE FIRST SELECTIVE DOPAMINE D-I A N T A G O N I S T JOHN HYTTEL Department of Pharmacology and Toxicology, H. Lundbeck & Co. A / S , Ottiliavej 7- 9, DK- 2500 Copenhagen - Valby, Denmark Received 30 May 1983, accepted 2 June 1983
Dopamine (DA) receptor-binding tests allow two different receptor populations to be measured. Receptors coupled to adenylate cyclase (AC) are termed D-1 whereas the receptors independent of AC are termed D-2. By using butyrophenone ligands, [3H]spiroperidol ([3H]SPI) or [3H]haloperidol ([3H]HAL), D-2 receptors are detected, whereas thioxanthene neuroleptics, [3H]cis(Z)flupentixol ([3H]FPT) and [3H]piflutixol ([3H]PIF) label the AC-dependent D-1 receptors (Hyttel, 1978, 1982). In displacement experiments, butyrophenones (haloperidol and spiroperidol), diphenylbutylpiperidines (pimozide) and benzamides (sulpiride) interact preferentially with D-2 receptors. In contrast thioxanthenes like cis(Z)flupentixol, cis(Z)-clopenthixol and cis(Z)-chlorprothixene have equal affinity for D-1 and D-2 receptors. Hitherto, no specific D-1 blocking compound has been found. In 1981, Ioris briefly described a benzazepine, SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro3-methyl-5-phenyl-IH-3-benzazepin-7-ol hemimaleate), with atypical effects on dopaminergic systems. His results indicated that SCH 23390 blocks postsynaptic DA receptor sites differentially and has little effect on presynaptic DA receptors. The present investigation was performed to characterize the neurochemical profile of SCH 23390. Male Wistar (Mol : Wist) rats, 150-200 g, were used. Inhibition of binding of [3H]-HAL and [3H]SPI to D-2 receptors in striatal membranes was measured as described by Hyttel (1978), except that for [3H]SPI the final pellet was homogenized in 200 volumes of buffer and the ligand concentration was 0.5 nM. [3H]PIF binding to
striatal D-1 receptors was measured as described by Hyttel (1982). Binding of [3H]prazosin ([3H]PRAZ) to al-receptors in membranes from brain and [3H]SPI to 5-HT 2 receptors in membranes from cortex was determined by methods analogous to the above mentioned. The ligand concentration was 0.25 nM and 0.5 nM for [3H]PRAZ and [3H]SPI binding, respectively. In the 5-HT 2 receptor binding experiments all samples contained 0.3 /.tM sulpiride to avoid binding to D-2 receptors. Inhibition of DA (40 #M)-stimulated AC activity was estimated in striatal homogenates as described by Hyttel (1978). SCH 23390 appears to be very potent inhibitor of [3H]PIF binding and AC activity (table 1) both markers for D-I receptors. SCH 23390 is equipotent with cis(Z)-flupentixol as an inhibitor of [3H]PIF binding. Whereas cis(Z)-flupentixol like other thioxanthenes - is equipotent on D-1 and D-2 receptors, SCH 23390 only possesses activity towards D-1 receptors. The effect on D-2 receptors ([-~H]HAL and [3H]SPI) is in the micromolar range. As has been described before (Hyttel, 1978, 1980) neuroleptics can be divided into selective D-2 antagonists and mixed D - l / D - 2 antagonists. As a selective D-1 antagonist SCH 23390 completes the list. Most neuroleptics also possess 5-HT 2 and a~-antagonistic effects (table 1). SCH 23390 has a smaller affinity to al-receptors than most others neuroleptics. However, SCH 23390 does possess some 5-HT 2 receptor blocking activity ([3H]SPI), although this effect is 23 times weaker than the effect on D-1 receptors ([3H]PIF). Since SCH 23390 is devoid of anticholinergic and antihistaminergic activity (J.-J. Larsen, personal com-
154 TABLE l Inhibitory effect of neuroleptics on different receptors in vitro. Receptor type Test system
D- 1 [3H]PIF
AC
D-2 [3H]HAL
[3H]SPI
5-HT2 [ s H]SPI
[ 3H]PRAZ
SCH 23390 cis(Z)-Flupentixol cis(Z)-Clopenthixol cis(Z)-Chlorprothixene Fluphenazine Perphenazine Haloperidol Spiroperidol Pimozide Sulpiride
1.3 1.4 9.8 16 14 31 430 2300 260 > 43000
11 1.5 2.2 2.0 5.5 11 19 100 160 47 000
2700 1.9 1.6 3.2 2. l 0.79 1.8 0.10 0.79 97
880 0.74 1.5 2.8 1.0 2.1 1.9 0.17 0.28 190
30 5.8 7.6 1.0 15 16 26 0.94 15 25 000
690 3.3 3.0 1.4 15 9.0 14 8.3 36 13000
K i
values in nM derived from the equation K i = IC50/1 × s/K m) are shown.
m u n i c a t i o n ) the c o m p o u n d m u s t be c o n s i d e r e d a very specific D-1 antagonist. It has previously b e e n shown that the antistereo t y p i c effect of neuroleptics which selectively inhibits D-2 receptors (e.g. haloperidol, p i m o z i d e ) is a t t e n u a t e d b y c o n c o m i t a n t t r e a t m e n t with anticholinergics, G A B A - e r g i c s or d i a z e p a m (Christensen et al., 1979). In c o n t r a s t the effect of neuroleptics which also possess p o t e n t D-1 receptor a n t a g o n i s t i c activities is h a r d l y influenced b y this treatment. P r e l i m i n a r y results in this l a b o r a t o r y (A.V. Christensen, p e r s o n a l c o m m u n i c a t i o n ) show that the m e t h y l p h e n i d a t e a n t a g o n i s t i c effect of S C H 23390 is slightly a t t e n u a t e d b y a G A B A agonist ( T H I P ) b u t n o t b y s c o p o l a m i n e o r diazepam. A f t e r p r o l o n g e d t r e a t m e n t with neuroleptics, tolerance to the m e t h y l p h e n i d a t e antagonistic effet is d e v e l o p e d after ' D - 2 selective' neuroleptics whereas such tolerance is b a r e l y seen after D - l / D 2 active neuroleptics (Christensen a n d Hyttel, 1982). P r e l i m i n a r y results indicate that neiter tolerance n o r increase in D-1 or D-2 r e c e p t o r n u m b e r develop after p r o l o n g e d t r e a t m e n t of mice with S C H 23390. In s u m m a r y , S C H 23390 is a very p o t e n t a n d selective D A D-1 r e c e p t o r a n t a g o n i s t with margin a l effect on D-2 d o p a m i n e r g i c , a~-adrenergic, m u s c a r i n i c a n d histaminergic receptors a n d with o n l y a slight effect on 5 - H T 2 receptors. S C H 23390
is thus the first selective D-1 d o p a m i n e r g i c a n t a g o n i s t to be described. U n d o u b t e d l y , S C H 23390 will be an i m p o r t a n t e x p e r i m e n t a l tool in further research on neuroleptics.
Acknowledgements I thank Dr. L.C, Iorio at Schering Corporation for the generous gift of SCH 23390.
References Christensen, A.V., J. Arnt and J. Scheel-Krtiger, 1979, Decreased antistereotypic effect of neurleptics after additional treatment with a benzodiazepine, a GABA-agonist and an anticholinergic compound, Life Sci. 24, 1395. Christensen, A.V. and J. Hyttel, 1982, Neuroleptics and the clinical implications of adaptation of dopamine neurons, Pharmacy International, 3, 329. Hyttel, J., 1978, Effects of neuroleptics on 3H-haloperidol and 3H-cis(Z)-flupenthixol binding and on adenylate cyclase activity in vitro, Life Sci., 23, 55 I. Hyttel, J., 1982, Preferential labelling of adenylate cyclase coupled dopamine receptors with thioxanthene neuroleptics, in: Advances in Dopamine Research, eds. M. Kohsaka, T. Shomori, Y. Tsukada and G.N. Woodruff (Pergamon Press, Oxford), p. 147. Iorio, L.C., 1981, SCH 23390, A benzazepine with atypical effects on dopaminergic systems, The Pharmacologist, 23, 136.
153
Rapid communication SCH 23390 - THE FIRST SELECTIVE DOPAMINE D-I A N T A G O N I S T JOHN HYTTEL Department of Pharmacology and Toxicology, H. Lundbeck & Co. A / S , Ottiliavej 7- 9, DK- 2500 Copenhagen - Valby, Denmark Received 30 May 1983, accepted 2 June 1983
Dopamine (DA) receptor-binding tests allow two different receptor populations to be measured. Receptors coupled to adenylate cyclase (AC) are termed D-1 whereas the receptors independent of AC are termed D-2. By using butyrophenone ligands, [3H]spiroperidol ([3H]SPI) or [3H]haloperidol ([3H]HAL), D-2 receptors are detected, whereas thioxanthene neuroleptics, [3H]cis(Z)flupentixol ([3H]FPT) and [3H]piflutixol ([3H]PIF) label the AC-dependent D-1 receptors (Hyttel, 1978, 1982). In displacement experiments, butyrophenones (haloperidol and spiroperidol), diphenylbutylpiperidines (pimozide) and benzamides (sulpiride) interact preferentially with D-2 receptors. In contrast thioxanthenes like cis(Z)flupentixol, cis(Z)-clopenthixol and cis(Z)-chlorprothixene have equal affinity for D-1 and D-2 receptors. Hitherto, no specific D-1 blocking compound has been found. In 1981, Ioris briefly described a benzazepine, SCH 23390 ((R)-(+)-8-chloro-2,3,4,5-tetrahydro3-methyl-5-phenyl-IH-3-benzazepin-7-ol hemimaleate), with atypical effects on dopaminergic systems. His results indicated that SCH 23390 blocks postsynaptic DA receptor sites differentially and has little effect on presynaptic DA receptors. The present investigation was performed to characterize the neurochemical profile of SCH 23390. Male Wistar (Mol : Wist) rats, 150-200 g, were used. Inhibition of binding of [3H]-HAL and [3H]SPI to D-2 receptors in striatal membranes was measured as described by Hyttel (1978), except that for [3H]SPI the final pellet was homogenized in 200 volumes of buffer and the ligand concentration was 0.5 nM. [3H]PIF binding to
striatal D-1 receptors was measured as described by Hyttel (1982). Binding of [3H]prazosin ([3H]PRAZ) to al-receptors in membranes from brain and [3H]SPI to 5-HT 2 receptors in membranes from cortex was determined by methods analogous to the above mentioned. The ligand concentration was 0.25 nM and 0.5 nM for [3H]PRAZ and [3H]SPI binding, respectively. In the 5-HT 2 receptor binding experiments all samples contained 0.3 /.tM sulpiride to avoid binding to D-2 receptors. Inhibition of DA (40 #M)-stimulated AC activity was estimated in striatal homogenates as described by Hyttel (1978). SCH 23390 appears to be very potent inhibitor of [3H]PIF binding and AC activity (table 1) both markers for D-I receptors. SCH 23390 is equipotent with cis(Z)-flupentixol as an inhibitor of [3H]PIF binding. Whereas cis(Z)-flupentixol like other thioxanthenes - is equipotent on D-1 and D-2 receptors, SCH 23390 only possesses activity towards D-1 receptors. The effect on D-2 receptors ([-~H]HAL and [3H]SPI) is in the micromolar range. As has been described before (Hyttel, 1978, 1980) neuroleptics can be divided into selective D-2 antagonists and mixed D - l / D - 2 antagonists. As a selective D-1 antagonist SCH 23390 completes the list. Most neuroleptics also possess 5-HT 2 and a~-antagonistic effects (table 1). SCH 23390 has a smaller affinity to al-receptors than most others neuroleptics. However, SCH 23390 does possess some 5-HT 2 receptor blocking activity ([3H]SPI), although this effect is 23 times weaker than the effect on D-1 receptors ([3H]PIF). Since SCH 23390 is devoid of anticholinergic and antihistaminergic activity (J.-J. Larsen, personal com-
154 TABLE l Inhibitory effect of neuroleptics on different receptors in vitro. Receptor type Test system
D- 1 [3H]PIF
AC
D-2 [3H]HAL
[3H]SPI
5-HT2 [ s H]SPI
[ 3H]PRAZ
SCH 23390 cis(Z)-Flupentixol cis(Z)-Clopenthixol cis(Z)-Chlorprothixene Fluphenazine Perphenazine Haloperidol Spiroperidol Pimozide Sulpiride
1.3 1.4 9.8 16 14 31 430 2300 260 > 43000
11 1.5 2.2 2.0 5.5 11 19 100 160 47 000
2700 1.9 1.6 3.2 2. l 0.79 1.8 0.10 0.79 97
880 0.74 1.5 2.8 1.0 2.1 1.9 0.17 0.28 190
30 5.8 7.6 1.0 15 16 26 0.94 15 25 000
690 3.3 3.0 1.4 15 9.0 14 8.3 36 13000
K i
values in nM derived from the equation K i = IC50/1 × s/K m) are shown.
m u n i c a t i o n ) the c o m p o u n d m u s t be c o n s i d e r e d a very specific D-1 antagonist. It has previously b e e n shown that the antistereo t y p i c effect of neuroleptics which selectively inhibits D-2 receptors (e.g. haloperidol, p i m o z i d e ) is a t t e n u a t e d b y c o n c o m i t a n t t r e a t m e n t with anticholinergics, G A B A - e r g i c s or d i a z e p a m (Christensen et al., 1979). In c o n t r a s t the effect of neuroleptics which also possess p o t e n t D-1 receptor a n t a g o n i s t i c activities is h a r d l y influenced b y this treatment. P r e l i m i n a r y results in this l a b o r a t o r y (A.V. Christensen, p e r s o n a l c o m m u n i c a t i o n ) show that the m e t h y l p h e n i d a t e a n t a g o n i s t i c effect of S C H 23390 is slightly a t t e n u a t e d b y a G A B A agonist ( T H I P ) b u t n o t b y s c o p o l a m i n e o r diazepam. A f t e r p r o l o n g e d t r e a t m e n t with neuroleptics, tolerance to the m e t h y l p h e n i d a t e antagonistic effet is d e v e l o p e d after ' D - 2 selective' neuroleptics whereas such tolerance is b a r e l y seen after D - l / D 2 active neuroleptics (Christensen a n d Hyttel, 1982). P r e l i m i n a r y results indicate that neiter tolerance n o r increase in D-1 or D-2 r e c e p t o r n u m b e r develop after p r o l o n g e d t r e a t m e n t of mice with S C H 23390. In s u m m a r y , S C H 23390 is a very p o t e n t a n d selective D A D-1 r e c e p t o r a n t a g o n i s t with margin a l effect on D-2 d o p a m i n e r g i c , a~-adrenergic, m u s c a r i n i c a n d histaminergic receptors a n d with o n l y a slight effect on 5 - H T 2 receptors. S C H 23390
is thus the first selective D-1 d o p a m i n e r g i c a n t a g o n i s t to be described. U n d o u b t e d l y , S C H 23390 will be an i m p o r t a n t e x p e r i m e n t a l tool in further research on neuroleptics.
Acknowledgements I thank Dr. L.C, Iorio at Schering Corporation for the generous gift of SCH 23390.
References Christensen, A.V., J. Arnt and J. Scheel-Krtiger, 1979, Decreased antistereotypic effect of neurleptics after additional treatment with a benzodiazepine, a GABA-agonist and an anticholinergic compound, Life Sci. 24, 1395. Christensen, A.V. and J. Hyttel, 1982, Neuroleptics and the clinical implications of adaptation of dopamine neurons, Pharmacy International, 3, 329. Hyttel, J., 1978, Effects of neuroleptics on 3H-haloperidol and 3H-cis(Z)-flupenthixol binding and on adenylate cyclase activity in vitro, Life Sci., 23, 55 I. Hyttel, J., 1982, Preferential labelling of adenylate cyclase coupled dopamine receptors with thioxanthene neuroleptics, in: Advances in Dopamine Research, eds. M. Kohsaka, T. Shomori, Y. Tsukada and G.N. Woodruff (Pergamon Press, Oxford), p. 147. Iorio, L.C., 1981, SCH 23390, A benzazepine with atypical effects on dopaminergic systems, The Pharmacologist, 23, 136.