Many dopamine-receptor antagonists displaying marginal selectivity for one of the classical subtypes of dopamine receptors exist. Most of the classical neuroleptics belong to them, e.g. the well-known phenothiazine chlorpromazine (41). Thioxanthenes, such as cis-flupentixol (42) and cis-clopentixol (43), are mostly mentioned as the prototypical mixed Dl/D2-receptor antagonists [13].

A well-known dopamine-receptor antagonist exerting considerable selectivity for the D2-receptor is the butyrophenone spiperone (44) [13,165,240]. However, this compound displays additionally high affinty for the serotonin 5-HT2 receptor [241].

Chart 1.12 Chemical structures of the phenothiazine chlorpromazine (41), the thioxanthenes cis- flupentixol(42) and cis-clopentixol(43), and the butyrophenone spiperone (44).

Chart 1.13 Chemical structures of (8-(-)-sulpiride (45), other benzamidederived selective D2-receptor antagonists (46-51) and clozapine (52), up-to-now the most selective D4-receptor agent.

Hence, highly selective D2-receptor antagonists were not available until the introduction of sulpiride (45) [242,243]. The D2-receptor antagonist activity of this agent was shown to reside exclusively in the (3-(-)-enantiomeric form. A disadvantage of (9-sulpiride (45) is its modest in vivo activity, which, in part, results from its fairly hydrophilic properties. Improved analogues of (5')-sulpiride (45), as far as lipophilicity is concerned, are remoxipride (46) and raclopride (47) [244-2461. Importantly, D2- receptor antagonists of extremely high affinity and selectivity belong also to this class of benzamides, e.g. ioxipride (NCQ 298, 48) [246,247]. Benzamides with other nitrogen-containing side chains are also highly selective Dpreceptor antagonists, e.g.

clebopride (49), emonapride (YM-09151-2, 50), and tropapride (51) [248-2501.

Recently, emonapride (50) was shown to bind nonselectively at the dopamine "D2-like"

receptors, i.e. the D2, D3, and D4 receptors (see 1.2.4) [149,159]. In contrast, raclopride (47) binds only with high affinity at the D2 and D3 receptors 1126,136,149, 1591, whereas remoxipride (46) binds merely at the D2 receptor, altough not very potently [126,144,149]. In this respect, the antipsychotic clozapine (52) should be mentioned as the most selective Dq-receptor agent presently known [126,136,144,149].

Based on their unique biochemical (increase of dopamine synthesis and release) and behavioural (moderate stimulation of activity instead of induction of hypomotility) profile the cis-I-methyl-5-methoxy-2-aminotetralins (+)-AJ 76 (53) and (+)-UH 232 (54) were characterized as D2-receptor antagonists with an apparent preference for the

Chart 1.14 Chemical structures of the apparent preferential dopamine-autoreceptor antagonists (+)-AJ 76 (53), (+)-UH 232 (54), and (-)-DS 121 (55).

D2 autoreceptor [251-2531. Moreover, recently, (+)-AJ 76 (53) and (+)-UH 232 (54) were shown the only agents among those classified as dopamine-receptor antagonists to possess a higher affinity at the D3 receptor than at the D2 receptor (about 4-fold) [136, 144,1461. Hence, their peculiar pharmacology may be a consequence of their limited Dyreceptor selectivity. Hypothetically, their weak behavioural stimulation may result from the selective blockade of an inhibitory postsynaptic D3 receptor [198b-198d], thereby enhancing the action of endogenous dopamine on a stimulatoly postsynaptic D2 receptor. Another compound belonging to the same class of agents is the lately described 3-phenylpiperidine (-)-DS 12 1 (55) [ 146,254,2551.

The (R)-SKI? 3 8393(29)-related benzazepines SCH 23390 (56) and (R)-SKF 83566 (SCH 24543, 57) were the first discovered dopamine-receptor antagonists interacting selectively with the D 1 receptor 1224,256-2591. Nowadays, many selective D 1 -receptor

Chart 1.15 Chemical structures of the selective Dl-receptor antagonists SCH 23390 (56), (R)-SKF 83566 (57), NNC 0756 (58), NNC 0687 (59), SCH 39166 (60), 4-(4-chloro-3-hydroxy- pheny1)-N-methyl- 1,2,3,4-tetra hydro is^ (61), and SDZ 2 1 1-534 (62).

antagonists exist, which are somehow analogues of SCH 23390 (56) or incorporate the structural elements of SCH 23390 (56) in a Dl-receptor agonist skeleton, chemical different fiom (R)-SKF 38393 (29). The benzazepines NNC 0756 (58) and NNC 0687 (59) as well as the hexahydrobenzonaphthazepine SCH 39166 (60) are examples of the first category [260,261], while the 4'-chloro-N-methyl analogue (61) of the tetrahydro- isoquinoline DPTI (35) as well as the hexahydrobenzophenanthridine SDZ 211-534 (62) are examples of the second category [169,262].

1.4 Dl/D2-RECEPTOR INTERACTIONS

Since the classification of dopamine receptors into Dl and D2 receptors (see 1.2.2), considerable attention has been devoted to the elucidation of the relative roles of these two dopamine-receptor subtypes in the mediation of biochemical, neurophysiological and behavioural effects of dopamine and dopamine-receptor agonists. During the first years after this classification the D2-receptor was believed to be the physiologically functional and clinically important entity. This was mainly due to the impressive correlation between the D2-receptor affiity of neuroleptics and their clinical effectiveness [263, 2641. Beside the mediation of the dopamine-induced stimulation of adenylyl cyclase activity, no functional role was assigned to the D l receptor. In fact, the Dl-receptor was described as a "receptor in search of a function" [ l 11. This view led to the development of selective D2-receptor agonists and antagonists for the treatment of Parkinson's disease [e. g. N-043 7 (1 4) and (+)-PHNO (2 I)] and schizophrenia [e. g.

remoxipride (46) and raclopride (47)], respectively [15].

However, since the introduction of selective Dl-receptor antagonists, the perspectives on the functional roles of dopamine-receptor subtypes changed radically (for reviews and references, see ref. 13,265-269). It was shown that selective Dl- receptor antagonists inhibit not only the typical biochemical (stimulation of CAMP- formation) and spontaneous behavioural effects (induction of grooming) of selective Dl-receptor agonists, but also exert potent behavioural effects (e.g. induction of hypolocomotion and catalepsy) similar to those of mixed DlID2-receptor antagonists as well as selective D2-receptor antagonists. Furthermore, it was revealed that these agents inhibit the typical spontaneous behavioural effects (e.g. induction of hyperlocomotion and stereotyped behaviours) of mixed DliD2-receptor agonist as well as selective D2- receptor agonists. On the basis of these findings, especially the last finding of

"behavioural nonselective dopamine-receptor antagonism", it was proposed that D l and D2 receptors often do not act independently, but rather interact functionally to mediate the effects of dopamine.

Subsequently, in studies clarifying further the role of functional Dl/D2-receptor interactions in the totality of dopaminergic function, it was reported for animals with normosensitive dopamine receptors that not only at the behavioural level, but also at

other levels, e.g. the biochemical level, two forms of D ~ / D ~ r e c e p t o r interactions exist, cooperative/synergistic D1/D2-receptor interactions and oppositional DllD2-receptor interactions [270-2721. In contrast, it was shown for animals with supersensitive dopamine receptors that, at least at the behavioural level, dopamine-receptor agonist- induced effects are mediated by functionally uncoupled Dl and D2 receptors. The next sections on functional DlID2-receptor interactions at the biochemical as well as the behavioural level have the intention to outline the current status of these Dl/D2- receptor interactions and to inform about their potential implications for basal ganglia movement disorders, such as Parkinson's disease. However, due to the overwhelming number of studies concerning biochemical and behavioural D 11D2-receptor interactions, these sections are not all-embracing. In addition, keeping in mind the present molecular biological multiplicity of the dopamine-receptor family, it is obvious that all studies concerning Dl/D2-receptor interactions may have involved any or all of the members within the currently proposed subfamilies of dopamine receptors, i. e. the dopamine

"Dl-like" and "D2-like" receptor subfamilies (see 1.2.4).

1.4.2 BIOCHEMICAL Dl/D2-RECEPTOR INTERACTIONS

The first described receptor interaction was an example of functional antagonism at the biochemical level. The discovery that a selective D2-receptor agonist possesses the ability to reduce the Dl-receptor agonist-evoked stimulation of CAMP formation in the rat striatum was done very soon after the classification of dopamine receptors into D 1 and D2 receptors [23]. Subsequently, several studies using selective Dl- and D2-receptor antagonists confirmed the contention that D l and D2 receptors interact in an opposing manner to regulate the activity of adenylyl cyclase in the striatum [24-263. Consequently, this interaction is presently looked upon as the prototypical biochemical Dl/D2-receptor interaction of the oppositional form.

For almost two decades now, it is evident that mesostriatal dopamine neurons make synaptic contacts with striatal acetylcholine interneurons and that released dopamine directly regulates the activity of these neurons in an inhibitory way (for review and references, see ref. 273). In vitro as well as in vivo experiments executed during the last decade revealed that the dopamine receptor mediating the inhibition of the striatal release of acetylcholine possesses the characteristics of a D2 receptor, whereas the activation of striatal Dl receptors has no influence on t . s release. This observation agrees well with the fact that striatal acetylcholine interneurons express primarily D2- receptor mRNA (see 1.2.4) [111,134]. Lately, however, in vivo microdialysis studies indicated that systemic administration of a selective Dl-receptor agonist increases the striatal release of acetylcholine [274,275]. Hence, it was speculated that this increase of the striatal release of acetylcholine is mediated by a Dl receptor located outside the striatum. Additionally, it was shown that systemic administration of indirectly acting dopamine-receptor agonists, like amphetamine and nomifensine (see 1.1.3), induce a

qualitatively similar increase of this release [276]. This increase, presumably dependent on Dl-receptor stimulation, was shown to be prevented by the administration of a NMDA-receptor antagonist [276,277]. Hence, glutamate neurons projecting to the striatum are likely involved in the Dl-receptor mediated increase of the striatal release of acetylcholine. Based on the fact that intranigral infusion of a selective Dl-receptor agonist increases the striatal release of acetylcholine but not of dopamine [277], it was suggested that D 1 receptors located in the substantia nigra pars reticulata (SNr) play an important role in this increase. Taken all these findings together, it is presently believed that dopamine regulates the activity of striatal acetylcholine intemeurons, not only directly by an inhibitory synaptic contact involving the stimulation of striatal D2 receptors, but also indirectly by a stimulatory multisynaptic pathway involving the stimulation of nigral D l receptors, as shown in Figure 1.6. Thus, at the neuronal circuitry level D l and D2 receptors interact functionally oppositionally to regulate the activity of striatal acetylcholine interneurons.

- I

GLU I

- 1

1

DAA;

GI 1

SNc GABA

SNr

Figure 1.6 Schematic representation of dopaminergic regulation of activity of striatal acetylcholine intemeurons. Abbreviations: ACh, acetylcholine; D 1, D 1 receptor; D2, D2 receptor; DA, dopamine; GABA, y-aminobutync acid; GLU, glutamate; SNc, substantia nigra pars compacts; SNr, substantia nigra pars reticulata.

Nowadays, it is also well recognized that dopamine exerts opposing effects on the extracellular levels of striatal GABA, very likely released ma~nly by recurrent collaterals of striatal G B A output neurons (for reviews and references, see ref. 278, 279). Particularly, Dl-receptor stimulation leads to an enhancement of the striatal release of GAEiA, whereas D2-receptor stimulation results in a reduction of this release [280,28 11. However, it is very likely not a question of interacting D l and D2 receptors at the cellular level, but it reflects most probably differential effects of dopamine on subpopulations of striatal GABA output neurons. In fact, it is currently believed that

dopamine activates via D 1 receptors the striatal GABAfsubstance Pldynorphin output neurons projecting to the internal segment of the globus pallidus (GPi) (equivalent to the rodent entopeduncular nucleus) and the substantia nigra pars reticulata (SNr), whereas it inhibits via D2 receptors the striatal GABAIenkephalin output neurons projecting to the external segment of the globus pallidus (GPe) (equivalent to the rodent globus pallidus) (Figure 1.7). This hypothesis is not only based on the predominant autoradiographical localization of D l receptors on striatonigral neurons and D2 receptors on striatopallidal neurons [282], but also on the respective expression of Dl- receptor and D2-receptor mRNA by these neurons (however, a subset of striatal output neurons expresses both Dl and D2 receptors) [109,110,134,135]. Moreover, support for this hypothesis was gained from the recent observations that under conditions of impaired dopaminergic neurotransmission the expression of substance P and Dl- receptor mRNA in striatonigral neurons is decreased and the expression of enkephalin and D2-receptor mRNA in striatopallidal neurons is increased; decreases and increases, reversed by the administration of a Dl-receptor agonist and a D2-receptor agonist, respectively [109]. However, although the stimulation of Dl and D2 receptors causes very likely opposing effects on the activities of striatonigral and striatopallidal GABA output neurons, the ultimate effect is most probably the same. In particular, the induction of decreased activity of neurons originating from the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi) via the "direct"

striatonigral pathway involving D l receptors and the "indirect" striatonigral pathway involving D2 receptors results (see 1.4.4).

pathway pathway

G Pe

STN SNrJGPi

Figure 1.7 Schematic representation of dopaminergic regulation of activity of striatal GABA output neurons. Abbreviations: Dl, Dl receptor; D2, D2 receptor; DA, dopamine; DYN, dynorphin; ENK, enkephalin; GABA, y-aminobutpc acid; GLU, glutamate; GPe, external segment of globus pallidus; GPi, internal segment of globus pallidus; SNc, substantia nigra pars compacts; SNr, substantia nigra pars reticuIata; SP, substance P; STN, subthalamic nucleus.

Recently, in addition to these oppositional biochemical D I@-receptor interactions biochemical D 1JD~receptor interactions of the cooperative/synergistic form have been described. The first report on such an interaction concerned the regulation by dopamine of the activity of the enzyme (Na+/K+)ATPase, an integral membrane protein coupling the hydrolysis of ATP to the countertransport of Na+ and K+ ions across the plasma membrane. A large portion of cellular energy in neurons is consumed by t h ~ s enzyme to maintain the ionic gradients that underlie resting and action potentials. Dopamine was shown to inhibit the (Na+/K+)ATPase activity of isolated striatal neurons through a synergistic effect on D l and D2 receptors at the single cell level [283]. However, the molecular basis for this synergistic Dl/D2-receptor interaction was unclear. Due to the fact that D l and D2 receptors interact in an opposing manner to regulate the activity of adenylyl cyclase, another unidentified signal transduction system was hypothesized to be responsible for the observed synergism [283].

Not much later, it was established that the activation of the arachldonic acid cascade by dopamine could serve as a molecular basis for biochemical Dl&-receptor interactions of the cooperative/synergistic form at the cellular level [147,284,285].

Stimulation of Dl receptors was shown to provide a synergistic contribution to the D2- receptor mediated potentiation of ~a2+-stimulated arachidonic acid release from CHO cells, in whch cloned D l as well as D2 receptors were expressed [147]. Since arachidonic acid is a potent inhibitor of the enzyme (Na+/K+)ATPase, its formation may account for the synergistic inhibition by dopamine of the (Na+/K+)-ATPase activity in striatal neurons [283].

1.4.3 BEHAVIOURAL Dl/D2-RECEPTOR INTERACTIONS

The finding that a selective Dl-receptor antagonist possesses the ability to inhibit the typical spontaneous behavioural effects induced by a selective D2-receptor agonist, such as hyperlocomotion and stereotyped sniffing [286-2881, was the frrst indication that D l and D2 receptors do not invariably act independently, but rather interact functionally in the mediation of typical spontaneous dopaminergic behaviours (for reviews and references, see ref. 13,265-269). Another piece of evidence in support of this contention was the inverse finding that a selective D2-receptor antagonist can inhibit grooming, a typical spontaneous behavioural effect induced by a selective Dl- receptor agonist [288-2901. Both findings exemplify "behavioural nonselective dopamine-receptor antagonism".

Additional validation of this concept resulted from studies in which the behavioural effects of selective dopamine-receptor agonists were compared with those of non- selective dopamine-receptor agonists and those of combinations of selective dopamine- receptor agonists in normal as well as acutely dopamine-depleted rats. These studies showed that for the expression of typical spontaneous dopaminergic behaviours stimulation of both subtypes of doparnine receptors is necessary [288,29 1-2961. In particular, a selective dopamine-receptor agonist is almost totally deprived of

behavioural effects in rats acutely depleted of dopamine by the tyrosine hydroxylase inhibitor a-methyl-p-tyrosine (AMPT). Hence, it was concluded that the typical spontaneous behavioural effects induced by selective Dl-receptor agonists, such as grooming, and by selective D2-receptor agonists, such as hyperlocomotion and mild stereotyped behaviour, in normal rats depend on the concurrent stimulation of the complementary dopamine receptor by endogenous dopamine. In addition, it was revealed that intense stereotyped behaviour, including continuous compulsive licking, biting, and gnawing, can only be induced in normal as well as acutely dopamine- depleted rats by a mixed DlD2-receptor agonist or a combination of a selective Dl- receptor agonist and a selective D2-receptor agonist. Thus, D l and D2 receptors interact functionally cooperatively or synergistically in the mediation of typical spontaneous dopaminergic behaviours, although the nature of the typical spontaneous behaviour depends on the ratio of simultaneous stimulation of both subtypes of dopamine receptors. Moreover, grooming is a mainly Dl-receptor-mediated behaviour, "enabledl permitted" by some tonic activity through D2 receptors, whereas hyperlocomotion and mild stereotyped behaviour are mamly D~receptor-mediated behaviours, "enabled permitted by some tonic activity through Dl receptors. In contrast, intense oral stereotyped behaviour is mediated by almost equally stimulated Dl and D2 receptors.

Recently, this concept was extended with behavioural Dl@-receptor interactions of the oppositional form. Nowadays, two forms of atypical motor behaviour, i.e.

vacuous chewing and myoclonic limbhody jerking, appear to have pharmacological profiles consistent with oppositional rather than cooperative/synergistic behavioural DlD2-receptor interactions [270-2721. Thus, vacuous chewing occurs most reliably when D l receptors are stimulated, while tonic activity through D2 receptors is suppressed; conversely, myoclonic limbhody jerking takes place when D2 receptors are stimulated, while tonic activity through Dl receptors is suppressed.

Beside in the mediation of typical spontaneous dopaminergic behaviours of normal animals, D l and D2 receptors appear to interact functionally cooperatively1 synergistically in the mediation of dopamine-receptor agonist-induced behaviours of manipulated animals, provided that normosensitive dopamine receptors are involved.

For instance, it was shown that for the induction of turning behaviour in rats with a unilateral striatal lesion elicited by the excitotoxin quinolinic acid [297], or with a complete hemitransection at a level caudal to the striaturn [298], or with unilateral inactivated striatal dopamine receptors by the irreversible receptor blocker N-ethoxy- carbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) [299] the concurrent stimulation of both subtypes of dopamine receptors is required. Due to the unilateral blockade of striatal output, the turning behaviour in these models is mediated by normosensitive dopamine receptors at the intact hemisphere, and therefore of ipsilateral nature (i.e.

circling towar& the blocked side). Additionally, it was revealed that in mice rendered acutely akinetic with the dopamine depletor reserpine (3 to 4 h before administration of dopamine-receptor agents), thus still possessing normosensitive dopamine receptors,

maximal locomotor activity can only be induced by the simultaneous stimulation of both D 1 and D2 receptors [300-3031.

In contrast, it was shown that in rodents rendered akinetic by either a chronic treatment (3 to 5 consecutive days before administration of dopamine-receptor agents) or a nonacute singular treatment with reserpine (e.g. 24 h before administration of dopamine-receptor agents), thus possessing to a greater or less extent supersensitive dopamine receptors through adaptational changes, it is suff~cient to stimulate only one of the classical subtypes of dopamine receptors to induce maximal locomotor activity [303,304]. This locomotor activity could only be antagonized by the corresponding selective dopamine-receptor antagonist ("behavioural selective dopamine-receptor antagonism"). Likewise, it was reported that in rats rendered akinetic by bilateral lesions of mesostriatal dopamine neurons by the neurotoxin 6-hydroxydopamine (6- OHDA) maximal hyperactivity could be induced by either a selective Dl-receptor agonist or a selective D2-receptor agonist, and consequently, antagonized by blocking the analogous dopamine receptor [305]. Hence, it seems that manipulated animals with supersensitive dopamine receptors display dopaminergic behaviours through functionally uncoupled D l and D2 receptors. Otherwise stated, D l and D2 receptors appear to act independently in the mediation of dopamine-receptor agonist-induced behaviours of manipulated animals when supersensitive dopamine receptors are involved. However, the molecular mechanism behind this functional uncoupling of D l and D2 receptors after induction of supersensitivity remains still unclear.

Accordingly, many studies have been executed in relation to probably the most widely used rodent model of Parkinson's disease, i. e. contralateral turning behaviour in rats with a unilateral 6-OHDA-lesion of the mesostriatal dopamine system, to elucidate the relative roles of D l and D2 receptors in the mediation of this behaviour (for reviews and references, see ref. 13,306). This rodent model of Parkinson's disease depends on the unilateral destruction of mesostriatal dopamine neurons due to the formation of toxic products by the oxidation of 6-OHDA to a reactive para-quinone. Consequently, this denervation leads at the lesioned side to supersensitivity of the postsynaptic striatal dopamine receptors. Hence, a directly acting dopamine-receptor agonist, like apomor- phine, induces contralateral turning behaviour (i. e. circling away from the lesioned side) through the preferential stimulation of these supersensitive dopamine receptors.

Some studies showed that this contralateral turning behaviour is mediated through synergistically interacting D l and D2 receptors [307,308], whereas other studies revealed that this behaviour is mediated through independently acting D l and D2 receptors. These receptors are likely uncoupled as a result of the development of supersensitivity [309-3 121. The contradicto~y findings could result from the dissimilar criteria used to select the rats, which are allowed to enter the experiments. The fust group of studies used generally a much higher test dose of apomorphine to induce in the

Some studies showed that this contralateral turning behaviour is mediated through synergistically interacting D l and D2 receptors [307,308], whereas other studies revealed that this behaviour is mediated through independently acting D l and D2 receptors. These receptors are likely uncoupled as a result of the development of supersensitivity [309-3 121. The contradicto~y findings could result from the dissimilar criteria used to select the rats, which are allowed to enter the experiments. The fust group of studies used generally a much higher test dose of apomorphine to induce in the

In document University of Groningen The 2-aminotetralin system as a structural base for new dopamine- and melatonin-receptor agents Copinga, Swier (Page 31-62)

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