Neurochem. Int. Vol. 20, Suppl., pp. 211S-214S, 1992
0197-0186/92 $5.00+0.00
Printed in GreatBritain
PergamonPresspie
STRUCTURE ACTIVITY RELATIONSHIP A N D T H E R A P E U T I C USES OF D O P A M I N E R G I C ERGOTS R. MARKSTEIN,M. P. SELLER,A. JATONand U. BRINER Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland
No other class of compounds exhibits such a widespread spectrum of structural diversity, biological activity and therapeutic uses as ergot derivatives. The common structural element of ergots is the tetracyclic ergoline ring system (figure 1 [3]). Mainly on the basis of the type of substituent at position 8 in the ergoline moiety ergots have been subdivided into structural classes such as clavines, lysergic acid derivatives, ergolines or ergopeptines. For the sake of simplicity the term ergoline is used for all compounds containing an ergoline ring except those carrying a tricyclic peptide ring at position 8 for which the term ergopeptine is used. The ergoline ring system bears a structural relationship to indole- and catecholarnines which explains why ergot derivatives exhibit affinity to recognition sites for serotonin, noradrenaline and dopamine. In recent years ergots with dopaminomimetic properties attracted great interest because of their potential to treat neurological and endocrine disorders. Bromocriptine was the first dopaminomimetic ergot which found widespread use in the treatment of Parkinson's disease and hyperprolactinemia. In the mean time a great variety of ergot derivatives have been synthesised which differ in selectivity and efficacy at D-1 and D-2 receptors. There exist also ergot derivatives which exhibit the properties of potent dopamine receptor antagonists, expanding the clinical use of this class of compounds into the treatment of schizophrenia. This short overview describes some novel dopaminergic ergot derivatives and their possible therapeutic uses and tries to explain some structure activity relationships with the rotamer-based dopamine receptor model. Stimulation of adenylate cyclase in homogenates of bovine retina and inhibition of electrically evoked acetylcholine release from rat striatal slices are used as functional responses mediated by D - I and D-2 receptor subtypes, respectively (Markstein, 1986). Ergolines
The ergoline ring itself exhibits dopaminomimetic properties. For instance, 6-methylergoline stimulates
dopamine sensitive adenylate cyclase with the same potency as dopamine whereas the activity at D-2 receptors inhibiting acetylcholine release in the striatum is almost negligible. Replacement of the methyl by a propyl group at N 6 markedly enhances the activity at D-2 receptors whereas the activity at the D 1 receptor remains unchanged or is even reduced. CQ 32-084 and its N-propyl derivative CQP 201-403 provide another example showing that the activity of ergolines at D-2 receptors is enhanced by elongation of the N6-alkyl substituent. In contrast, alkyl or halogen substituents in position 2 reduce the efficacy both at D-1 and D-2 receptors but often increase the affinity. For example, bromination in position 2 converts the mixed D - I / D - 2 agonist d-LSD or the potent D-2 agonist Lisuride into pure dopamine antagonists (BOL-148 [2b] and Bromerguride [4b]). Recently, several types of 2-substituted ergolines have been synthesised which exhibit the properties of dopamine receptor partial agonists. Partial agonists with low intrinsic activity at dopamine receptors can act as synaptic "buffers" by reducing dopaminergic activity when it is excessive and promoting it when it is reduced. Such a profile might be a novel principle for the treatment of schizophrenia. The antipsychotic activity of neuroleptics is thought to be based on their ability to block dopamine receptors in the mesolimbic system whereas blockade of dopamine receptors in the basal ganglia and pituitary might be responsible for extrapyramidal side effects and hyperprolactinemia frequently observed during treatment with classical neuroleptics. High potency, low efficacy partial dopamine receptor agonists might be effective in this illness but, due to their weak agonistic component, not produce extrapyramidal or endocrine side effects. The question how much intrinsic activity at dopamine receptors is possible to avoid exacerbation of psychosis and how much intrinsic activity is needed to prevent extrapyramidal side effects can only be answered after clinical evaluation of a series of partial agonists differing in their intrinsic activity. Interestingly, Lisuride exhibits the properties of a partial D-2 receptor agonist in vitro (Markstein et al.,1988). The fact that
211S
212S
Dopamine 90
Lisuride is effective in Parkinson patients where it can also produce psychiatric side effects (Lieberman et a1.,1983) suggests that its efficacy at D-2 receptors is too high to be useful for the treatment in schizophrenia. Terguride, the 9,10-transdihydro derivative of Lisuride exhibits a much lower efficacy than Lisuride in the acetylcholine release test and potently antagonises the effect ofapomorphine. This dualistic effect in vitro is also expressed in vivo. It inhibits prolactin secretion and induces circling behaviour in rats with unilateral 6-OHDA-induced lesion in the substantia nigra (Ungerstedt rats), which is consistent with agonistic effects at D-2 receptors. On the other hand, Terguride, like classical neuroleptics, induces catalepsy and blocks apomorphine-induced gnawing in rats. It is presently unclear whether the efficacy of Terguride at D-2 receptors is low enough to permit its use in schizophrenia, bearing in mind that it is effective in Parkinson patients (Suchy et al.,1986). Bromerguride [4b], the 2-bromo derivative of Lisuride is devoid of stimulant properties at dopamine receptors. It induces catalepsy, potently inhibits apomorphine-induced gnawing and increases prolactin secretion in rats, suggesting that its properties are close to those of classical neuroleptics (Wachtel et al., 1983). Bromerguride has been reported to diminish positive symptoms in schizophrenic patients (Wachtel and Sauer,1988). SDZ HDC-912 [5b] and SDZ MAR-327 [5c] are two novel, 8-alpha-ergolines exhibiting the properties of dopamine receptor partial agonists with lower efficacy than Terguride (Coward et al., 1989). The efficacy of both compounds is too low to be detectable in the acetylcholine release model. Both compounds antagonise apomorphine-induced gnawing in rats as potent as haloperidol. SDZ M A R 327 produces no catalepsy and SDZ HDC-912 only at a dose at least 20 times higher than that blocking apomorphine-induced gnawing in rats. Although the efficacy of SDZ HDC-912 at D-2 receptors is too low to be detectable in vitro it inhibits prolactin secretion in rats and induces circling behaviour of moderate intensity in Ungerstedt rats. SDZ MAR-327 differs from SDZ HDC-912 by a weaker prolactin lowering activity but a stronger effect in Ungerstedt rats. Based on these results, SDZ H D C 912 and SDZ MAR-327 seem to posses pharmacological properties intermediate between those of Bromerguride and Terguride and may therefore be suitable for the treatment of schizophrenia without inducing extrapyramidal and endocrine side effects. These compounds are presently under clinical evaluation.
Benzergolines
CY 208-243 [6A] is a new compound containing an ergoline moiety linked to a benzol ring, which exhibits the properties of a selective D-1 receptor agonist. It stimulates dopamine-sensitive adenylate cyclase and fails to inhibit striatal acetylcholine relea~ m a spiperone sensitive manner. Surprisingly, CY 208 243 is relatively potent in displacing radioligands from D .... 2 receptor recognition sites. The selectivity ratio for displacing agonistic ligands from D - I and D-2 recognition sites is 12 in favour of the D-1 site. Despite this relatively low selectivity in ligand binding studies CY 208-243 produces no effects indicating an effect on D-2 receptors in functional in vitro tests or in animals. CY 208-243 induces contralateral circling behaviour in Ungerstedt rats which is blocked by the D-1 antagonist SCH 23390 but not by the D-2 antagonist sulpiride. It has no effect on prolactin secretion in rats, induces no emesis in dogs and has no effect on dopamine synthesis in the rat striatum. Similar effects have been reported for the selective D-1 agonist SKF 38393 (Setler et al.,1978). However, CY 208-243, in contrast to SKF 38393, exhibits antiparkinson activity in MPTP-treated monkeys and Parkinson patients (Temlett et al., 1989). As is shown in table 1 replacement of the hydrogen atom at N 6 in the benzergoline structure by methyl, ethyl or propyl diminishes the activity at D-1 receptors with increasing chain length without greatly altering the effect at D 2 receptors. This is in contrast to the situation in ergolines where elongation of N6-alkyl groups enhances the activity at D-2 receptors. Ergopeptines
The influence of substituents at position 2 and the nitrogen atom in position 6 observed in ergolines cannot be transferred to ergopeptines. For instance, alpha-ergokryptine exhibits in vitro the profile of a mixed D - I / D - 2 agonist. Alkyl or halogen substituents at position 2 enhances affinity and efficacy at D-2 receptors where as the affinity is retained at D - I receptors. In the case of halogen substituents the intrinsic activity at the D-1 receptor is abolished. CBM 36-733 is another example showing that a methyl substituent in position 2 enhances the activity at D-2 receptors (table 1). Interestingly, elongation of the alkyl substituent at N 6 from methyl to ethyl enhances the intrinsic activity at the D-1 receptor. This again is opposite to the findings in the ergoline class. These observations suggest that ergopeptines interact with the dopamine receptor in a different manner than ergolines.
213S
D o p a r a i n e 90 o H-
C--NH---
:
o .... >
0197-0186/92 $5.00+0.00
Printed in GreatBritain
PergamonPresspie
STRUCTURE ACTIVITY RELATIONSHIP A N D T H E R A P E U T I C USES OF D O P A M I N E R G I C ERGOTS R. MARKSTEIN,M. P. SELLER,A. JATONand U. BRINER Preclinical Research, Sandoz Pharma Ltd, 4002 Basel, Switzerland
No other class of compounds exhibits such a widespread spectrum of structural diversity, biological activity and therapeutic uses as ergot derivatives. The common structural element of ergots is the tetracyclic ergoline ring system (figure 1 [3]). Mainly on the basis of the type of substituent at position 8 in the ergoline moiety ergots have been subdivided into structural classes such as clavines, lysergic acid derivatives, ergolines or ergopeptines. For the sake of simplicity the term ergoline is used for all compounds containing an ergoline ring except those carrying a tricyclic peptide ring at position 8 for which the term ergopeptine is used. The ergoline ring system bears a structural relationship to indole- and catecholarnines which explains why ergot derivatives exhibit affinity to recognition sites for serotonin, noradrenaline and dopamine. In recent years ergots with dopaminomimetic properties attracted great interest because of their potential to treat neurological and endocrine disorders. Bromocriptine was the first dopaminomimetic ergot which found widespread use in the treatment of Parkinson's disease and hyperprolactinemia. In the mean time a great variety of ergot derivatives have been synthesised which differ in selectivity and efficacy at D-1 and D-2 receptors. There exist also ergot derivatives which exhibit the properties of potent dopamine receptor antagonists, expanding the clinical use of this class of compounds into the treatment of schizophrenia. This short overview describes some novel dopaminergic ergot derivatives and their possible therapeutic uses and tries to explain some structure activity relationships with the rotamer-based dopamine receptor model. Stimulation of adenylate cyclase in homogenates of bovine retina and inhibition of electrically evoked acetylcholine release from rat striatal slices are used as functional responses mediated by D - I and D-2 receptor subtypes, respectively (Markstein, 1986). Ergolines
The ergoline ring itself exhibits dopaminomimetic properties. For instance, 6-methylergoline stimulates
dopamine sensitive adenylate cyclase with the same potency as dopamine whereas the activity at D-2 receptors inhibiting acetylcholine release in the striatum is almost negligible. Replacement of the methyl by a propyl group at N 6 markedly enhances the activity at D-2 receptors whereas the activity at the D 1 receptor remains unchanged or is even reduced. CQ 32-084 and its N-propyl derivative CQP 201-403 provide another example showing that the activity of ergolines at D-2 receptors is enhanced by elongation of the N6-alkyl substituent. In contrast, alkyl or halogen substituents in position 2 reduce the efficacy both at D-1 and D-2 receptors but often increase the affinity. For example, bromination in position 2 converts the mixed D - I / D - 2 agonist d-LSD or the potent D-2 agonist Lisuride into pure dopamine antagonists (BOL-148 [2b] and Bromerguride [4b]). Recently, several types of 2-substituted ergolines have been synthesised which exhibit the properties of dopamine receptor partial agonists. Partial agonists with low intrinsic activity at dopamine receptors can act as synaptic "buffers" by reducing dopaminergic activity when it is excessive and promoting it when it is reduced. Such a profile might be a novel principle for the treatment of schizophrenia. The antipsychotic activity of neuroleptics is thought to be based on their ability to block dopamine receptors in the mesolimbic system whereas blockade of dopamine receptors in the basal ganglia and pituitary might be responsible for extrapyramidal side effects and hyperprolactinemia frequently observed during treatment with classical neuroleptics. High potency, low efficacy partial dopamine receptor agonists might be effective in this illness but, due to their weak agonistic component, not produce extrapyramidal or endocrine side effects. The question how much intrinsic activity at dopamine receptors is possible to avoid exacerbation of psychosis and how much intrinsic activity is needed to prevent extrapyramidal side effects can only be answered after clinical evaluation of a series of partial agonists differing in their intrinsic activity. Interestingly, Lisuride exhibits the properties of a partial D-2 receptor agonist in vitro (Markstein et al.,1988). The fact that
211S
212S
Dopamine 90
Lisuride is effective in Parkinson patients where it can also produce psychiatric side effects (Lieberman et a1.,1983) suggests that its efficacy at D-2 receptors is too high to be useful for the treatment in schizophrenia. Terguride, the 9,10-transdihydro derivative of Lisuride exhibits a much lower efficacy than Lisuride in the acetylcholine release test and potently antagonises the effect ofapomorphine. This dualistic effect in vitro is also expressed in vivo. It inhibits prolactin secretion and induces circling behaviour in rats with unilateral 6-OHDA-induced lesion in the substantia nigra (Ungerstedt rats), which is consistent with agonistic effects at D-2 receptors. On the other hand, Terguride, like classical neuroleptics, induces catalepsy and blocks apomorphine-induced gnawing in rats. It is presently unclear whether the efficacy of Terguride at D-2 receptors is low enough to permit its use in schizophrenia, bearing in mind that it is effective in Parkinson patients (Suchy et al.,1986). Bromerguride [4b], the 2-bromo derivative of Lisuride is devoid of stimulant properties at dopamine receptors. It induces catalepsy, potently inhibits apomorphine-induced gnawing and increases prolactin secretion in rats, suggesting that its properties are close to those of classical neuroleptics (Wachtel et al., 1983). Bromerguride has been reported to diminish positive symptoms in schizophrenic patients (Wachtel and Sauer,1988). SDZ HDC-912 [5b] and SDZ MAR-327 [5c] are two novel, 8-alpha-ergolines exhibiting the properties of dopamine receptor partial agonists with lower efficacy than Terguride (Coward et al., 1989). The efficacy of both compounds is too low to be detectable in the acetylcholine release model. Both compounds antagonise apomorphine-induced gnawing in rats as potent as haloperidol. SDZ M A R 327 produces no catalepsy and SDZ HDC-912 only at a dose at least 20 times higher than that blocking apomorphine-induced gnawing in rats. Although the efficacy of SDZ HDC-912 at D-2 receptors is too low to be detectable in vitro it inhibits prolactin secretion in rats and induces circling behaviour of moderate intensity in Ungerstedt rats. SDZ MAR-327 differs from SDZ HDC-912 by a weaker prolactin lowering activity but a stronger effect in Ungerstedt rats. Based on these results, SDZ H D C 912 and SDZ MAR-327 seem to posses pharmacological properties intermediate between those of Bromerguride and Terguride and may therefore be suitable for the treatment of schizophrenia without inducing extrapyramidal and endocrine side effects. These compounds are presently under clinical evaluation.
Benzergolines
CY 208-243 [6A] is a new compound containing an ergoline moiety linked to a benzol ring, which exhibits the properties of a selective D-1 receptor agonist. It stimulates dopamine-sensitive adenylate cyclase and fails to inhibit striatal acetylcholine relea~ m a spiperone sensitive manner. Surprisingly, CY 208 243 is relatively potent in displacing radioligands from D .... 2 receptor recognition sites. The selectivity ratio for displacing agonistic ligands from D - I and D-2 recognition sites is 12 in favour of the D-1 site. Despite this relatively low selectivity in ligand binding studies CY 208-243 produces no effects indicating an effect on D-2 receptors in functional in vitro tests or in animals. CY 208-243 induces contralateral circling behaviour in Ungerstedt rats which is blocked by the D-1 antagonist SCH 23390 but not by the D-2 antagonist sulpiride. It has no effect on prolactin secretion in rats, induces no emesis in dogs and has no effect on dopamine synthesis in the rat striatum. Similar effects have been reported for the selective D-1 agonist SKF 38393 (Setler et al.,1978). However, CY 208-243, in contrast to SKF 38393, exhibits antiparkinson activity in MPTP-treated monkeys and Parkinson patients (Temlett et al., 1989). As is shown in table 1 replacement of the hydrogen atom at N 6 in the benzergoline structure by methyl, ethyl or propyl diminishes the activity at D-1 receptors with increasing chain length without greatly altering the effect at D 2 receptors. This is in contrast to the situation in ergolines where elongation of N6-alkyl groups enhances the activity at D-2 receptors. Ergopeptines
The influence of substituents at position 2 and the nitrogen atom in position 6 observed in ergolines cannot be transferred to ergopeptines. For instance, alpha-ergokryptine exhibits in vitro the profile of a mixed D - I / D - 2 agonist. Alkyl or halogen substituents at position 2 enhances affinity and efficacy at D-2 receptors where as the affinity is retained at D - I receptors. In the case of halogen substituents the intrinsic activity at the D-1 receptor is abolished. CBM 36-733 is another example showing that a methyl substituent in position 2 enhances the activity at D-2 receptors (table 1). Interestingly, elongation of the alkyl substituent at N 6 from methyl to ethyl enhances the intrinsic activity at the D-1 receptor. This again is opposite to the findings in the ergoline class. These observations suggest that ergopeptines interact with the dopamine receptor in a different manner than ergolines.
213S
D o p a r a i n e 90 o H-
C--NH---
:
o .... >
