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Partial agonism of dopamine, serotonin and opiate receptors for psychiatry
Drug Discovery Today: Therapeutic Strategies
Vol. 3, No. 4 2006
Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Nervous system disorders
Partial agonism of dopamine, serotonin and opiate receptors for psychiatry Frank Yocca1, C. Anthony Altar2,* 1 2
Psychiatry Discovery, AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, USA Psychiatric Genomics, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA
Most psychiatric diseases are treated with pharmacological receptor antagonists. The efficacy of recently approved partial agonists and their relatively good safety profiles suggest an alternative strategy for drug discovery. Aripiprazole (Abilify) treats schizophrenia
Section Editors: David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA C. Anthony Altar – Psychiatric Genomics, Gaithersburg, USA Theresa Branchek – Lundbeck Research, Paramus, USA
through partial agonism of D2/3 dopamine receptors, buspirone (Buspar) treats anxiety or depression by partial agonism of the 5-HT1A receptor and partial opiate or dopamine agonists treat opiate and stimulant addictions. Predictions of other receptor targets for intervention by partial agonists provide a test for the broader utility of this pharmacological approach. Introduction Silent receptor antagonists function as drugs in the central nervous system (CNS) by binding to receptors and blocking the postsynaptic intracellular signaling caused by endogenous agonist ligands (Fig. 1). This has been particularly relevant to the treatment of psychiatric disease, as evidenced by the success of monoamine transport reuptake receptor blockers for treating depression (see article by Skolnick and Basile, this volume) and by the uniform blockade of the D2/3 class of dopamine receptors by first- or second-generation antipsychotics [1]. An emerging class of successful CNS agents, the partial agonists, is demonstrating the advantages of signal attenuation at single or multiple receptors. These compounds treat psychiatric disease or addiction, and do so with increased patient compliance, diminished side effects com*Corresponding author: C.A. Altar ([email protected]) 1740-6773/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2006.10.014
pared with silent antagonists, broader dose ranges for clinical response, and penetration into sometimes crowded therapeutic areas by virtue of their distinct clinical profiles. This review describes partial agonists of the D2/3, serotonin 1A (5-HT1A) and opioid receptor classes and their recent successes in treating schizophrenia, substance abuse and anxiety or depression. Other clinical opportunities for partial agonists are proposed for future drug discovery efforts.
Partial agonists for psychosis Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperanizyl]butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an efficacious drug for the treatment for schizophrenia and does not induce significant extrapyramidal symptoms, elevations in serum prolactin, weight gain, type II diabetes or sedation [2–4]. Aripiprazole affinities for the D2/3 dopamine receptor and other monoaminergic receptors (Fig. 2) would not by themselves predict such a differential clinical profile, except perhaps for the potent binding to various serotonin receptors [5,6]. Rather than blocking D2, D3 and 5-HT1A receptors, however, aripiprazole is a partial agonist of these receptors [7–9]. Because agonism of the D2 receptor is negatively coupled to the formation of the second messenger, cyclic adenosine monophosphate (cAMP), the degree of D2 agonism by a novel agent can be evaluated by its ability to reverse the increase of 429
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Figure 1. Localization of terminal autoreceptors and signal-transducing postsynaptic D2/3 and 5-HT1A receptors for dopamine and serotonin. Heteroreceptors are pre- or postsynaptic receptors for ligands other than the one(s) released presynaptically.
cAMP induced even by nonspecific drugs like forskolin. For example, the full D2/D3 agonist dopamine reverses all of the forskolin-induced increases in cAMP in Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells that express the hD2 receptor [8]. Aripiprazole reverses only about 30–80% of such cAMP accumulations in either cell line, depending upon the degree of D2 occupancy [8]. Such a modest level of intrinsic D2 efficacy is preferable to high intrinsic agonism, as exemplified by (3-(3-hydroxyphenyl)N-n-propylpiperidine) (3-PPP); [10,11] and other early clinical entries in the partial agonist field, including CGS 15855 [12]. 3-PPP can improve negative symptoms of schizophrenia but at the expense of exacerbating the positive symptoms and inducing tolerance with prolonged use. In preclinical in vivo rodent models, oral doses of aripiprazole can produce D2 antagonist effects by blocking apomorphine-induced stereotypy or climbing. Importantly, these effects occur at doses up to 12-fold lower than those that
Figure 2. The most potent binding affinities of aripiprazole to neurotransmitter receptors and transport recognition sites. The data include those from [6,9,53]. Abbreviations: a, alpha adrenergic; D, dopamine receptor; DAT, NET, SERT: dopamine, norepineprhine and serotonin transporters, respectively; 5-HT, serotonin; M, muscarinic, H, histamine.
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induce catalepsy [13–15]. These separations between efficacy and side-effect doses resemble those of oral doses of the highly effective, atypical antipsychotic drug clozapine. These separations exceed those of the ‘typical’, or extrapyramidal side-effect prone, antipsychotic drugs, including chlorpromazine, haloperidol and even other ‘atypical’ antipsychotics, which are less likely to induce extrapyramidal side effects, namely, risperidone and olanzapine [16]. Aripiprazole can produce D2 agonist activity in a model of extreme dopaminergic hypoactivity (blockade of increased dopamine synthesis in reserpine-treated rats) [13]. These properties confirm the prediction of Carlsson [10,11] that D2 partial agonists would attenuate hyperdopaminergic conditions and improve positive symptoms. Whether such drugs, including aripiprazole, can augment D2 signaling during hypodopaminergic conditions and improve cognitive symptoms, remains to be proven. The low incidence of side effects including Parkinsonian-like motor symptoms or changes in serum prolactin [17], was predicted from the less than complete blockade of striatal (Fig. 3, top) and pituitary (Fig. 3, bottom) D2 receptors by aripiprazole. 5-HT1A receptor stimulation has been demonstrated for ziprasidone, mazapertine, nemonapride, quetiepine [5,16,18–21], clozapine [9,22] and was first discovered for aripiprazole by Jordan et al. [9]. The 5-HT1A stimulation by aripiprazole is a potent, but partial, agonist stimulation, as determined with the binding of [35S]-labeled guanosine triphosphate ([35S]-GTPgS; [9]. Importantly, the partial 5-HT1A agonism of these agents often occur at concentrations similar to their binding affinities at hD2 receptors [6,22]. Partial 5-HT1A agonists such as buspirone are anxiolytic. This receptor action, if produced by an antipsychotic drug, could ameliorate affective components of psychosis, such as anxiety and negative symptoms [5,23]. The ability of 5-HT1A receptor activation to increase cortical dopamine release [24] may underlie the effectiveness of clozapine and ziprasidone against the negative symptoms of schizophrenia. 5-HT1A receptor agonism can also diminish the catalepsy induced
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Figure 3. Pre- and postsynaptic mechanisms of partial D2/3 agonism compared with silent D2/3 antagonism. (a) Ventral striatum left. Dopamine (DA; red balls) is made in and released from a dense plexus of nerve terminals in the striatum. Its interaction with presynaptic terminal autoreceptors (‘AR’; red hexagon) inhibits its own synthesis and release, and postsynaptic signaling results from its interaction with postsynaptic D2/3 receptors (blue hexagons). Middle: Atypical (olanzapine) or typical (haloperidol) antipsychotics acutely increase dopamine synthesis and release but these actions are blocked by their silent antagonism at postsynaptic receptors. Right: Partial dopamine D2 agonists, exemplified by aripiprazole, have little effect on dopamine synthesis or release and attenuate postsynaptic signaling. (b) Pituitary lactotroph left. A similar scheme applies to the pituitary lactotroph, except that dopamine nerve terminal densities, synthesis and release are at lower levels than in the striatum. The autoreceptor-like sensitivity of such under-stimulated D2 receptors may increase the functional activity of partial agonists [7,8]. Middle: D2 receptor blockade by olanzapine or haloperidol prevent the dopamine that is released from hypothalamic neurons to lower prolactin release. This elevates serum prolactin. Right: Aripiprazole does not elevate serum prolactin in humans, presumably owing to its lack of inhibition of pituitary lactotrophs [17,54] and postulated lesser effects on dopamine synthesis and release. These models are based on the literature including microdialysis studies [55–57].
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by D2 antagonists in rodents and primates [20,23]. Elevations in serum prolactin produced by D2 antagonists can be attenuated by partial 5-HT1A agonists. 5-HT1A partial agonism can also block conditioned avoidance responding in rats, and stereotypy and yawning induced by the D1/2 agonist, apomorphine. These actions are reminiscent of the clinical profile of aripiprazole, which includes efficacy against negative symptoms, minimal EPS, and no alteration in serum prolactin [2–4]. The fact that similar effects in animal models have been found with partial D2 agonists like 3-PPP suggests that dual partial agonism of 5-HT1A and D2 receptors may be a useful combination to promote the safe and efficacious treatment of psychosis.
Substance abuse Partial agonists have also proven to help substance abusers decrease their addictions to opiate agonists. Not surprisingly, the mainstays of this approach are partial agonists of the mu, delta and kappa classes of opiate receptors, because these mediate the addictive properties of full opiate agonists like morphine and heroin. One particularly successful agent, buprenorphine, is a partial mu agonist and silent antagonist at kappa receptors [25]. It is frequently administered with naloxone as an opioid partial agonist–antagonist combination for heroin addiction. Conversely, nalmefene is a partial kappa opiate agonist and silent antagonist of mu opioid receptors [26]. Whether nalmefene is as effective as buprenorphine in the treatment of heroin addiction may help determine the relative contributions of these two receptors, and degree of inherent agonism that is preferable in the treatment of opiate addiction. Although opiate receptors mediate the initial step in the addiction to full opiate receptor ligands, D2 and D3 dopamine receptors mediate the rewarding components of addictive drugs. An increase in the release of dopamine, and stimulation of D2/3 receptors in the shell of the nucleus accumbens, is a consistent property of addictive substances. Thus, it is perhaps not surprising that the D2/3 receptor partial agonists aripiprazole [27], terguride, SDZ 208911 [28,29] and the D3 partial agonist BP 897 [30,31] block the reinstatement of cocaine self-injection in rats or monkeys. Neither agent alone supports self-administration in either species and, in the rat, aripiprazole blocks reinstatement of cocaine self-injection at low doses (0.1 mg/kg) that fail to alter feeding, food-seeking behavior, or basal locomotion [27]. 5p, a structural analogue of BP 897, is a potent D3 partial agonist, and also blocks reinstatement of cocaine self-administration. Another BP 897 analogue, 5q, is a potent and selective D3 partial agonist but devoid of D2 activity. Its inability to effect cocaine-seeking behavior is consistent with the requirement of D2 receptors for relapse induction [29] and indicates that partial D2 agonism contributes to the reduction of stimulant craving by partial D3 agonists [29,32]. This is not surprising because 432
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almost all compounds that bind the D2 receptor also bind the D3 receptor with near-equal affinity. Thus, partial D2/3 agonists like aripiprazole, BP 897, terguride, and related drugs may be second-line approaches to treating addiction to opiates, and first-line approaches for reducing the craving and relapse self-administration of stimulant drugs, with little or no innate liability to support dependence. The ability of partial opiate and D2/3 receptors to attenuate drug craving suggests that partial agonism is a useful concept that can be applied broadly in treating substance addiction. Consistent with this hypothesis is preclinical and clinical effectiveness of the nicotinic receptor partial agonist varenicline against nicotine actions in the nucleus accumbens, and in smoking cessation. More research is needed to identify the critical receptor(s), and degree of partial agonism, that can optimize compliance and minimize side effects, tolerance and other undesirable properties that may occur with such potent partial agonists.
Anxiety and depression Buspirone, the prototype 5-HT1A partial agonist, was approved in 1986 for the treatment of anxiety. Buspirone was considered to be one of the most promising new anxiolytic agents. Originally synthesized as a psychosedative agent [33], early testing in conditioned avoidance responding in rats suggested potential efficacy in schizophrenia. However, buspirone was found to be devoid of antipsychotic activity in controlled clinical studies. A return to preclinical testing revealed a marked calming effect in aggressive monkeys [34]. These findings were also supported by studies in which mice were foot shocked to induce aggression, and in studies with rats subjected to shockinduced suppression of drinking behavior [35]. Buspirone inhibited aggression in mice and demonstrated an anxiolytic-like effect in the suppression of rat drinking behavior. These findings were the basis upon which buspirone was pursued clinically as a treatment for anxiety. Buspirone efficacy in the treatment of anxiety disorders has been clearly established in a variety of placebo-controlled trials. Goldberg and Finnerty [36] were the first to demonstrate the effective treatment of anxious patients by buspirone in a placebo-controlled trial. With an initial positive outcome in hand, three large, placebo-controlled clinical trials compared buspirone with diazepam. In each case, buspirone showed a significant benefit [37,38]. Importantly, patients with moderate to severe anxiety were successfully treated with buspirone in varied settings, including those of psychiatric and general medical practice. Furthermore, experience from these studies supported the excellent safety profile for buspirone in anxious patients. Clinically important CNS or other neurological toxicities were not encountered. The main side effects included dizziness, lightheadedness, nausea and headache. Unlike diazepam, there were no reports of sedation or drowsiness associated with buspirone treatment. Furthermore, initial side
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effects seemed to dissipate as the number of exposures to the drug increased. Although often overlooked, buspirone is effective in treating mixed anxiety and depression states. Robinson [39] evaluated efficacy of the drug in the treatment of depression from a series of five placebo-controlled, parallel group studies. Analyses of the composite data base from the five studies showed significant improvement in mean Hamilton rating scales for depression (HAM-D) and anxiety (HAM-A), and the Clinical Global Impression-Global Improvement (CGI) scale ratings for buspirone-treated compared with the placebotreated patients. Of particular interest was significant improvement in cardinal depression symptoms, for example, depressed mood, guilt, lower levels of work and interest, anergia, and diurnal variations of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms responded better to buspirone than did patients who suffered from mild to moderate depression. Importantly, and unlike the selective serotonin reuptake inhibitors (SSRIs), the efficacy seen in anxiety and depression with buspirone was not accompanied by any incidence in sexual side effects like delayed ejaculation, impotence or decreased sexual desire. The most potent molecular interaction of buspirone is with central pre- and postsynaptic 5-HT1A receptors (Fig. 1). Its clinical activity in anxiety and depression should not be surprising, given the abundance of data that suggest that alterations in central serotonergic function have been implicated in a variety of psychiatric illnesses, including anxiety and depression. Preclinical neurochemical studies indicate that buspirone, and other representatives of the once promising class of drugs known as azapirones (gepirone, ipsapirone, tandospirone) bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-HT1A receptors [40]. Although the affinity of buspirone is similar for preand postsynaptic 5-HT1A receptors [41], the efficacy exerted at these receptors appears to be different. At presynaptic 5-HT1A somatodendritic autoreceptors which control serotonin neuron impulse flow (see Fig. 1; [42], synthesis [42], and release [43], buspirone demonstrates a potent, robust agonist action. These studies demonstrated that systemic administration of buspirone potently and dose-dependently reduces 5-HT synthesis, release and impulse flow in rats through an agonist interaction with somatodendritic 5-HT1A receptors. These in vivo findings are supported by in vitro extracellular and intracellular electrophysiological studies which demonstrate that buspirone potently inhibits the firing of serotonin-containing dorsal raphe neurons (IC50 = 19 nM; [44]) and hyperpolarizes the dorsal raphe membrane in a concentration range of 200–400 nM and to a degree similar to that obtained with serotonin [45]. By contrast, buspirone demonstrates partial agonist activity at postsynaptic 5-HT1A receptors. It inhibits forskolin-
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stimulated adenylyl cyclase in rat hippocampal membranes [46]. Furthermore, in intracellular recordings on hippocampal pyramidal cells of the CA1 region, the maximal hyperpolarization induced by buspirone was significantly smaller than that induced by 5-HT. Because the buspirone-induced hyperpolarization was also accompanied by a surmountable antagonism of 5-HT responses, these results indicate that buspirone behaves as a partial agonist at 5-HT1A receptors in the cornu ammonis 1 (CA1) region of the hippocampus [47]. These results demonstrate the region-dependent difference in responses at pre- and postsynaptic 5-HT1A receptors. Studies by Meller et al. [48] and Yocca et al. [49] utilizing irreversible alkylation of the 5-HT1A receptor with EEDQ indicate that the difference in buspirone action can be attributed to a difference in 5-HT1A receptor reserve between somatodendritic and hippocampal 5-HT1A receptors. The partial agonist nature of buspirone at postsynaptic 5-HT1A receptors allows for speculation with regard to its clinical use in depression and anxiety and states of hyperand hyposerotonergic tone. This is a similar scenario to the one described above for aripiprazole, its interaction with the D2 receptor, and ability to treat schizophrenia. The varying degree of agonist activity at regionally distinct 5-HT1A receptors are most likely important to the production of adaptive changes in 5-HT neurotransmission that occur after chronic treatment, which may explain the delayed clinical onset for efficacy.
Future opportunities for partial agonists A successful partial agonist program requires extensive calibration of the receptor system of interest. This involves a model system (such as a cell line that expresses the human receptor), a measure of receptor agonist activity (such as a [35S]-GTPgS binding assay), and calibration of the system with known agonists and antagonist compounds that probably is hidden treasure in the form of potent but partial agonists. Their activity (maximal efficacy, or Emax) in the assay system can be related to their different clinical properties such as a favorable efficacy versus side effect ratio. This may identify an optimal degree of partial agonism for the clinical endpoint of interest. A drawback of this approach is its requirement of an existing pharmacopia of drugs and their responses. The efficacy of partial agonists in therapeutic areas for which only antagonists have been developed can be estimated using preclinical models that respond to antagonists. One example of where this can be applied is in the development of partial muscarinic agonists to treat schizophrenia. The ability of xanomeline to treat psychosis of Alzheimer’s disease appears to result from its agonism of muscarinic M1 receptors in brain. Unfortunately, the interaction of xanomeline with peripheral muscarinic receptors induces limiting autonomic side effects and development of this promising www.drugdiscoverytoday.com
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compound was halted. CS-932 [50] ameliorates scopolamineinduced memory deficits in rats, and is also an M1 partial agonist compared to the full agonist acetylcholine. Sabcomeline (SB-202026) is a functionally selective M1 receptor partial agonist that enhances cognition in non-human primate and at doses that do not alter blood pressure, emesis or other behaviors commonly associated with muscarinic agonists. It is interesting to consider that compounds with full M1 agonism and partial agonism of M2, M3 and other peripheral muscarinic receptors might better separate central effects on cognition and psychosis from peripherally mediated side effects. One such compound, BIMC 182, is a full agonist at M1 and a partial agonist at M2 and M3 sites [51]. Its low affinity at muscarinic sites may have precluded clinical efficacy [52].
Conclusion Partial agonists are effective treatments with desirable properties, but difficult to discover and develop for CNS diseases. Why is this? There is a state-dependency to their signaling effects. They can exert receptor stimulation when native hormone or neurotransmitter receptor stimulation is lacking, acting to reinstitute endogenous neurotransmission. This can occur in the absence of tolerance, reducing the potential for receptor desensitization. When excessive neurotransmission underlies the disease state, partial agonists with low intrinsic activity will act as functional antagonists, reducing tone without producing receptor supersensitivity, thereby minimizing potential side effects. For these reasons, variations in the stimulation of the target receptor by endogenous transmitter may vary the response to the partial agonist. Other reasons for the rare appearance of partial agonists in the pharmacopeia include the far greater emphasis on antagonist screening in most drug discovery efforts, the erroneous conclusions generated from singular assay approaches to define partial agonists, and the failure to use sufficiently broad numbers and types of reference compounds to define the degree of partial agonism for each assay used. The selective control of regionally distinct receptor responses is a new opportunity to maximize drug efficacy and minimize side effects. Human receptors transfected into kidney and ovary cells can model, but cannot replicate, the in situ differences in regional receptor systems responses to agonists (G-proteins, transduction pathways, receptor reserve, stoichiometry and so forth). This may require the use of native tissue for optimizing the structure-activity relationships of regional receptor efficacy and partial agonism. When technology allows this to be measured in vitro, the full potential of partial agonists as novel CNS drugs may be realized.
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Sharp, T. et al. (1989) 5-HT1A agonists reduce 5-HT release in rat hippocampus in vivo as determined by brain microdialysis. Br. J. Pharmacol. 96, 283–290 VanderMaelen, C.P. et al. (1991) Electrophysiological studies on the effects of buspirone on serotonergic neurons. In Buspirone: Mechanisms and Clinical Aspects (Tunnicliff, G. et al. eds), pp. 215–230, Academic Press Aghajanian, G.K. and Lakoski, J.M. (1984) Hyperpolarization of serotonergic neurons by serotonin and LSD: studies in brain slices showing increase K+ conductance. Brain Res. 305, 181–185 DeVivo, M. and Maayani, S. (1986) Characterization of the 5hydroxytryptamine 1A receptor-mediated inhibition of forskolinstimulated adenylate cyclase activity in guinea pig and rat hippocampal membranes. J. Pharmacol. Exp. Ther. 238, 248–253 Andrade, R. and Nicoll, R.A. (1987) Novel anxiolytics discriminate between postsynaptic serotonin receptors mediating different physiological responses on single neurons of the rat hippocampus. Naunyn-Schmiedeberg’s Arch. Pharmacol. 336, 5–10 Meller, E. et al. (1990) Receptor reserve for 5-hydroxytryptamine1Amediated inhibition of serotonin synthesis: possible relationship to anxiolytic properties of 5-hydroxytryptamine1A agonists. Mol. Pharmacol. 37, 231–237 Yocca, F.D. et al. (1992) Lack of apparent receptor reserve at postsynaptic 5-HT1A receptors negatively coupled to adenylyl cyclase activity in rat hippocampal membranes. Mol. Pharmacol. 41, 1066–1072 Iwata, N. et al. (2000) Activation of cerebral function by CS-932, a functionally selective M1 partial agonist: neurochemical characterization and pharmacological studies. Jpn. J. Pharmacol. 84, 266–280 Cereda, E. et al. (1994) Medicinal chemistry of muscarinic agonists for the treatment of dementia disorders. Eur. J. Drug Metab. Pharmacokinet. 19, 179–183 Harries, M.H. et al. (1998) The profile of sabcomeline (SB-202026), a functionally selective M1 receptor partial agonist, in the marmoset. Br. J. Pharmacol. 124, 409–415 Bymaster, F.P. et al. (1996) Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 14, 87–96 Inoue, A. et al. (1998) Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary. Brain Res. Mol. Brain Res. 55, 285–292 Semba, J. et al. (1995) Characterisation of extracellular amino acids in striatum of freely moving rats by in vivo microdialysis. J. Neural Transm. Gen. Sect. 100, 39–52 Nakai, S. et al. (2003) Diminished catalepsy and dopamine metabolism distinguish aripiprazole from haloperidol or risperidone. Eur. J. Pharmacol. 472, 89–97 Jordan, S. et al. (2004) In vivo effects of aripiprazole on cortical and striatal dopaminergic and serotonergic function. Eur. J. Pharmacol. 483, 45–53
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Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Nervous system disorders
Partial agonism of dopamine, serotonin and opiate receptors for psychiatry Frank Yocca1, C. Anthony Altar2,* 1 2
Psychiatry Discovery, AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850, USA Psychiatric Genomics, Inc., 19 Firstfield Road, Gaithersburg, MD 20878, USA
Most psychiatric diseases are treated with pharmacological receptor antagonists. The efficacy of recently approved partial agonists and their relatively good safety profiles suggest an alternative strategy for drug discovery. Aripiprazole (Abilify) treats schizophrenia
Section Editors: David Sibley – National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA C. Anthony Altar – Psychiatric Genomics, Gaithersburg, USA Theresa Branchek – Lundbeck Research, Paramus, USA
through partial agonism of D2/3 dopamine receptors, buspirone (Buspar) treats anxiety or depression by partial agonism of the 5-HT1A receptor and partial opiate or dopamine agonists treat opiate and stimulant addictions. Predictions of other receptor targets for intervention by partial agonists provide a test for the broader utility of this pharmacological approach. Introduction Silent receptor antagonists function as drugs in the central nervous system (CNS) by binding to receptors and blocking the postsynaptic intracellular signaling caused by endogenous agonist ligands (Fig. 1). This has been particularly relevant to the treatment of psychiatric disease, as evidenced by the success of monoamine transport reuptake receptor blockers for treating depression (see article by Skolnick and Basile, this volume) and by the uniform blockade of the D2/3 class of dopamine receptors by first- or second-generation antipsychotics [1]. An emerging class of successful CNS agents, the partial agonists, is demonstrating the advantages of signal attenuation at single or multiple receptors. These compounds treat psychiatric disease or addiction, and do so with increased patient compliance, diminished side effects com*Corresponding author: C.A. Altar ([email protected]) 1740-6773/$ ß 2006 Elsevier Ltd. All rights reserved.
DOI: 10.1016/j.ddstr.2006.10.014
pared with silent antagonists, broader dose ranges for clinical response, and penetration into sometimes crowded therapeutic areas by virtue of their distinct clinical profiles. This review describes partial agonists of the D2/3, serotonin 1A (5-HT1A) and opioid receptor classes and their recent successes in treating schizophrenia, substance abuse and anxiety or depression. Other clinical opportunities for partial agonists are proposed for future drug discovery efforts.
Partial agonists for psychosis Aripiprazole, 7-{4-[4-(2,3-dichlorophenyl)-1-piperanizyl]butyloxy}-3,4-dihydro-2(1H)-quinolinone, is an efficacious drug for the treatment for schizophrenia and does not induce significant extrapyramidal symptoms, elevations in serum prolactin, weight gain, type II diabetes or sedation [2–4]. Aripiprazole affinities for the D2/3 dopamine receptor and other monoaminergic receptors (Fig. 2) would not by themselves predict such a differential clinical profile, except perhaps for the potent binding to various serotonin receptors [5,6]. Rather than blocking D2, D3 and 5-HT1A receptors, however, aripiprazole is a partial agonist of these receptors [7–9]. Because agonism of the D2 receptor is negatively coupled to the formation of the second messenger, cyclic adenosine monophosphate (cAMP), the degree of D2 agonism by a novel agent can be evaluated by its ability to reverse the increase of 429
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Figure 1. Localization of terminal autoreceptors and signal-transducing postsynaptic D2/3 and 5-HT1A receptors for dopamine and serotonin. Heteroreceptors are pre- or postsynaptic receptors for ligands other than the one(s) released presynaptically.
cAMP induced even by nonspecific drugs like forskolin. For example, the full D2/D3 agonist dopamine reverses all of the forskolin-induced increases in cAMP in Chinese hamster ovary (CHO) or human embryonic kidney (HEK) cells that express the hD2 receptor [8]. Aripiprazole reverses only about 30–80% of such cAMP accumulations in either cell line, depending upon the degree of D2 occupancy [8]. Such a modest level of intrinsic D2 efficacy is preferable to high intrinsic agonism, as exemplified by (3-(3-hydroxyphenyl)N-n-propylpiperidine) (3-PPP); [10,11] and other early clinical entries in the partial agonist field, including CGS 15855 [12]. 3-PPP can improve negative symptoms of schizophrenia but at the expense of exacerbating the positive symptoms and inducing tolerance with prolonged use. In preclinical in vivo rodent models, oral doses of aripiprazole can produce D2 antagonist effects by blocking apomorphine-induced stereotypy or climbing. Importantly, these effects occur at doses up to 12-fold lower than those that
Figure 2. The most potent binding affinities of aripiprazole to neurotransmitter receptors and transport recognition sites. The data include those from [6,9,53]. Abbreviations: a, alpha adrenergic; D, dopamine receptor; DAT, NET, SERT: dopamine, norepineprhine and serotonin transporters, respectively; 5-HT, serotonin; M, muscarinic, H, histamine.
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induce catalepsy [13–15]. These separations between efficacy and side-effect doses resemble those of oral doses of the highly effective, atypical antipsychotic drug clozapine. These separations exceed those of the ‘typical’, or extrapyramidal side-effect prone, antipsychotic drugs, including chlorpromazine, haloperidol and even other ‘atypical’ antipsychotics, which are less likely to induce extrapyramidal side effects, namely, risperidone and olanzapine [16]. Aripiprazole can produce D2 agonist activity in a model of extreme dopaminergic hypoactivity (blockade of increased dopamine synthesis in reserpine-treated rats) [13]. These properties confirm the prediction of Carlsson [10,11] that D2 partial agonists would attenuate hyperdopaminergic conditions and improve positive symptoms. Whether such drugs, including aripiprazole, can augment D2 signaling during hypodopaminergic conditions and improve cognitive symptoms, remains to be proven. The low incidence of side effects including Parkinsonian-like motor symptoms or changes in serum prolactin [17], was predicted from the less than complete blockade of striatal (Fig. 3, top) and pituitary (Fig. 3, bottom) D2 receptors by aripiprazole. 5-HT1A receptor stimulation has been demonstrated for ziprasidone, mazapertine, nemonapride, quetiepine [5,16,18–21], clozapine [9,22] and was first discovered for aripiprazole by Jordan et al. [9]. The 5-HT1A stimulation by aripiprazole is a potent, but partial, agonist stimulation, as determined with the binding of [35S]-labeled guanosine triphosphate ([35S]-GTPgS; [9]. Importantly, the partial 5-HT1A agonism of these agents often occur at concentrations similar to their binding affinities at hD2 receptors [6,22]. Partial 5-HT1A agonists such as buspirone are anxiolytic. This receptor action, if produced by an antipsychotic drug, could ameliorate affective components of psychosis, such as anxiety and negative symptoms [5,23]. The ability of 5-HT1A receptor activation to increase cortical dopamine release [24] may underlie the effectiveness of clozapine and ziprasidone against the negative symptoms of schizophrenia. 5-HT1A receptor agonism can also diminish the catalepsy induced
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Figure 3. Pre- and postsynaptic mechanisms of partial D2/3 agonism compared with silent D2/3 antagonism. (a) Ventral striatum left. Dopamine (DA; red balls) is made in and released from a dense plexus of nerve terminals in the striatum. Its interaction with presynaptic terminal autoreceptors (‘AR’; red hexagon) inhibits its own synthesis and release, and postsynaptic signaling results from its interaction with postsynaptic D2/3 receptors (blue hexagons). Middle: Atypical (olanzapine) or typical (haloperidol) antipsychotics acutely increase dopamine synthesis and release but these actions are blocked by their silent antagonism at postsynaptic receptors. Right: Partial dopamine D2 agonists, exemplified by aripiprazole, have little effect on dopamine synthesis or release and attenuate postsynaptic signaling. (b) Pituitary lactotroph left. A similar scheme applies to the pituitary lactotroph, except that dopamine nerve terminal densities, synthesis and release are at lower levels than in the striatum. The autoreceptor-like sensitivity of such under-stimulated D2 receptors may increase the functional activity of partial agonists [7,8]. Middle: D2 receptor blockade by olanzapine or haloperidol prevent the dopamine that is released from hypothalamic neurons to lower prolactin release. This elevates serum prolactin. Right: Aripiprazole does not elevate serum prolactin in humans, presumably owing to its lack of inhibition of pituitary lactotrophs [17,54] and postulated lesser effects on dopamine synthesis and release. These models are based on the literature including microdialysis studies [55–57].
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by D2 antagonists in rodents and primates [20,23]. Elevations in serum prolactin produced by D2 antagonists can be attenuated by partial 5-HT1A agonists. 5-HT1A partial agonism can also block conditioned avoidance responding in rats, and stereotypy and yawning induced by the D1/2 agonist, apomorphine. These actions are reminiscent of the clinical profile of aripiprazole, which includes efficacy against negative symptoms, minimal EPS, and no alteration in serum prolactin [2–4]. The fact that similar effects in animal models have been found with partial D2 agonists like 3-PPP suggests that dual partial agonism of 5-HT1A and D2 receptors may be a useful combination to promote the safe and efficacious treatment of psychosis.
Substance abuse Partial agonists have also proven to help substance abusers decrease their addictions to opiate agonists. Not surprisingly, the mainstays of this approach are partial agonists of the mu, delta and kappa classes of opiate receptors, because these mediate the addictive properties of full opiate agonists like morphine and heroin. One particularly successful agent, buprenorphine, is a partial mu agonist and silent antagonist at kappa receptors [25]. It is frequently administered with naloxone as an opioid partial agonist–antagonist combination for heroin addiction. Conversely, nalmefene is a partial kappa opiate agonist and silent antagonist of mu opioid receptors [26]. Whether nalmefene is as effective as buprenorphine in the treatment of heroin addiction may help determine the relative contributions of these two receptors, and degree of inherent agonism that is preferable in the treatment of opiate addiction. Although opiate receptors mediate the initial step in the addiction to full opiate receptor ligands, D2 and D3 dopamine receptors mediate the rewarding components of addictive drugs. An increase in the release of dopamine, and stimulation of D2/3 receptors in the shell of the nucleus accumbens, is a consistent property of addictive substances. Thus, it is perhaps not surprising that the D2/3 receptor partial agonists aripiprazole [27], terguride, SDZ 208911 [28,29] and the D3 partial agonist BP 897 [30,31] block the reinstatement of cocaine self-injection in rats or monkeys. Neither agent alone supports self-administration in either species and, in the rat, aripiprazole blocks reinstatement of cocaine self-injection at low doses (0.1 mg/kg) that fail to alter feeding, food-seeking behavior, or basal locomotion [27]. 5p, a structural analogue of BP 897, is a potent D3 partial agonist, and also blocks reinstatement of cocaine self-administration. Another BP 897 analogue, 5q, is a potent and selective D3 partial agonist but devoid of D2 activity. Its inability to effect cocaine-seeking behavior is consistent with the requirement of D2 receptors for relapse induction [29] and indicates that partial D2 agonism contributes to the reduction of stimulant craving by partial D3 agonists [29,32]. This is not surprising because 432
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almost all compounds that bind the D2 receptor also bind the D3 receptor with near-equal affinity. Thus, partial D2/3 agonists like aripiprazole, BP 897, terguride, and related drugs may be second-line approaches to treating addiction to opiates, and first-line approaches for reducing the craving and relapse self-administration of stimulant drugs, with little or no innate liability to support dependence. The ability of partial opiate and D2/3 receptors to attenuate drug craving suggests that partial agonism is a useful concept that can be applied broadly in treating substance addiction. Consistent with this hypothesis is preclinical and clinical effectiveness of the nicotinic receptor partial agonist varenicline against nicotine actions in the nucleus accumbens, and in smoking cessation. More research is needed to identify the critical receptor(s), and degree of partial agonism, that can optimize compliance and minimize side effects, tolerance and other undesirable properties that may occur with such potent partial agonists.
Anxiety and depression Buspirone, the prototype 5-HT1A partial agonist, was approved in 1986 for the treatment of anxiety. Buspirone was considered to be one of the most promising new anxiolytic agents. Originally synthesized as a psychosedative agent [33], early testing in conditioned avoidance responding in rats suggested potential efficacy in schizophrenia. However, buspirone was found to be devoid of antipsychotic activity in controlled clinical studies. A return to preclinical testing revealed a marked calming effect in aggressive monkeys [34]. These findings were also supported by studies in which mice were foot shocked to induce aggression, and in studies with rats subjected to shockinduced suppression of drinking behavior [35]. Buspirone inhibited aggression in mice and demonstrated an anxiolytic-like effect in the suppression of rat drinking behavior. These findings were the basis upon which buspirone was pursued clinically as a treatment for anxiety. Buspirone efficacy in the treatment of anxiety disorders has been clearly established in a variety of placebo-controlled trials. Goldberg and Finnerty [36] were the first to demonstrate the effective treatment of anxious patients by buspirone in a placebo-controlled trial. With an initial positive outcome in hand, three large, placebo-controlled clinical trials compared buspirone with diazepam. In each case, buspirone showed a significant benefit [37,38]. Importantly, patients with moderate to severe anxiety were successfully treated with buspirone in varied settings, including those of psychiatric and general medical practice. Furthermore, experience from these studies supported the excellent safety profile for buspirone in anxious patients. Clinically important CNS or other neurological toxicities were not encountered. The main side effects included dizziness, lightheadedness, nausea and headache. Unlike diazepam, there were no reports of sedation or drowsiness associated with buspirone treatment. Furthermore, initial side
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effects seemed to dissipate as the number of exposures to the drug increased. Although often overlooked, buspirone is effective in treating mixed anxiety and depression states. Robinson [39] evaluated efficacy of the drug in the treatment of depression from a series of five placebo-controlled, parallel group studies. Analyses of the composite data base from the five studies showed significant improvement in mean Hamilton rating scales for depression (HAM-D) and anxiety (HAM-A), and the Clinical Global Impression-Global Improvement (CGI) scale ratings for buspirone-treated compared with the placebotreated patients. Of particular interest was significant improvement in cardinal depression symptoms, for example, depressed mood, guilt, lower levels of work and interest, anergia, and diurnal variations of mood. Subset analyses revealed that patients with melancholic-type major depression and patients with more severe symptoms responded better to buspirone than did patients who suffered from mild to moderate depression. Importantly, and unlike the selective serotonin reuptake inhibitors (SSRIs), the efficacy seen in anxiety and depression with buspirone was not accompanied by any incidence in sexual side effects like delayed ejaculation, impotence or decreased sexual desire. The most potent molecular interaction of buspirone is with central pre- and postsynaptic 5-HT1A receptors (Fig. 1). Its clinical activity in anxiety and depression should not be surprising, given the abundance of data that suggest that alterations in central serotonergic function have been implicated in a variety of psychiatric illnesses, including anxiety and depression. Preclinical neurochemical studies indicate that buspirone, and other representatives of the once promising class of drugs known as azapirones (gepirone, ipsapirone, tandospirone) bind selectively to presynaptic (dorsal raphe) and postsynaptic (hippocampus, cortex) 5-HT1A receptors [40]. Although the affinity of buspirone is similar for preand postsynaptic 5-HT1A receptors [41], the efficacy exerted at these receptors appears to be different. At presynaptic 5-HT1A somatodendritic autoreceptors which control serotonin neuron impulse flow (see Fig. 1; [42], synthesis [42], and release [43], buspirone demonstrates a potent, robust agonist action. These studies demonstrated that systemic administration of buspirone potently and dose-dependently reduces 5-HT synthesis, release and impulse flow in rats through an agonist interaction with somatodendritic 5-HT1A receptors. These in vivo findings are supported by in vitro extracellular and intracellular electrophysiological studies which demonstrate that buspirone potently inhibits the firing of serotonin-containing dorsal raphe neurons (IC50 = 19 nM; [44]) and hyperpolarizes the dorsal raphe membrane in a concentration range of 200–400 nM and to a degree similar to that obtained with serotonin [45]. By contrast, buspirone demonstrates partial agonist activity at postsynaptic 5-HT1A receptors. It inhibits forskolin-
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stimulated adenylyl cyclase in rat hippocampal membranes [46]. Furthermore, in intracellular recordings on hippocampal pyramidal cells of the CA1 region, the maximal hyperpolarization induced by buspirone was significantly smaller than that induced by 5-HT. Because the buspirone-induced hyperpolarization was also accompanied by a surmountable antagonism of 5-HT responses, these results indicate that buspirone behaves as a partial agonist at 5-HT1A receptors in the cornu ammonis 1 (CA1) region of the hippocampus [47]. These results demonstrate the region-dependent difference in responses at pre- and postsynaptic 5-HT1A receptors. Studies by Meller et al. [48] and Yocca et al. [49] utilizing irreversible alkylation of the 5-HT1A receptor with EEDQ indicate that the difference in buspirone action can be attributed to a difference in 5-HT1A receptor reserve between somatodendritic and hippocampal 5-HT1A receptors. The partial agonist nature of buspirone at postsynaptic 5-HT1A receptors allows for speculation with regard to its clinical use in depression and anxiety and states of hyperand hyposerotonergic tone. This is a similar scenario to the one described above for aripiprazole, its interaction with the D2 receptor, and ability to treat schizophrenia. The varying degree of agonist activity at regionally distinct 5-HT1A receptors are most likely important to the production of adaptive changes in 5-HT neurotransmission that occur after chronic treatment, which may explain the delayed clinical onset for efficacy.
Future opportunities for partial agonists A successful partial agonist program requires extensive calibration of the receptor system of interest. This involves a model system (such as a cell line that expresses the human receptor), a measure of receptor agonist activity (such as a [35S]-GTPgS binding assay), and calibration of the system with known agonists and antagonist compounds that probably is hidden treasure in the form of potent but partial agonists. Their activity (maximal efficacy, or Emax) in the assay system can be related to their different clinical properties such as a favorable efficacy versus side effect ratio. This may identify an optimal degree of partial agonism for the clinical endpoint of interest. A drawback of this approach is its requirement of an existing pharmacopia of drugs and their responses. The efficacy of partial agonists in therapeutic areas for which only antagonists have been developed can be estimated using preclinical models that respond to antagonists. One example of where this can be applied is in the development of partial muscarinic agonists to treat schizophrenia. The ability of xanomeline to treat psychosis of Alzheimer’s disease appears to result from its agonism of muscarinic M1 receptors in brain. Unfortunately, the interaction of xanomeline with peripheral muscarinic receptors induces limiting autonomic side effects and development of this promising www.drugdiscoverytoday.com
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compound was halted. CS-932 [50] ameliorates scopolamineinduced memory deficits in rats, and is also an M1 partial agonist compared to the full agonist acetylcholine. Sabcomeline (SB-202026) is a functionally selective M1 receptor partial agonist that enhances cognition in non-human primate and at doses that do not alter blood pressure, emesis or other behaviors commonly associated with muscarinic agonists. It is interesting to consider that compounds with full M1 agonism and partial agonism of M2, M3 and other peripheral muscarinic receptors might better separate central effects on cognition and psychosis from peripherally mediated side effects. One such compound, BIMC 182, is a full agonist at M1 and a partial agonist at M2 and M3 sites [51]. Its low affinity at muscarinic sites may have precluded clinical efficacy [52].
Conclusion Partial agonists are effective treatments with desirable properties, but difficult to discover and develop for CNS diseases. Why is this? There is a state-dependency to their signaling effects. They can exert receptor stimulation when native hormone or neurotransmitter receptor stimulation is lacking, acting to reinstitute endogenous neurotransmission. This can occur in the absence of tolerance, reducing the potential for receptor desensitization. When excessive neurotransmission underlies the disease state, partial agonists with low intrinsic activity will act as functional antagonists, reducing tone without producing receptor supersensitivity, thereby minimizing potential side effects. For these reasons, variations in the stimulation of the target receptor by endogenous transmitter may vary the response to the partial agonist. Other reasons for the rare appearance of partial agonists in the pharmacopeia include the far greater emphasis on antagonist screening in most drug discovery efforts, the erroneous conclusions generated from singular assay approaches to define partial agonists, and the failure to use sufficiently broad numbers and types of reference compounds to define the degree of partial agonism for each assay used. The selective control of regionally distinct receptor responses is a new opportunity to maximize drug efficacy and minimize side effects. Human receptors transfected into kidney and ovary cells can model, but cannot replicate, the in situ differences in regional receptor systems responses to agonists (G-proteins, transduction pathways, receptor reserve, stoichiometry and so forth). This may require the use of native tissue for optimizing the structure-activity relationships of regional receptor efficacy and partial agonism. When technology allows this to be measured in vitro, the full potential of partial agonists as novel CNS drugs may be realized.
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