Anti-emetic effects o
`f a novel NK-1 receptor antagonist HSP-117 in ferrets;
`(1998)
`254 ESNELT 3 169-172
`October 2, 1998
`Section: Pgs.
`169-172 Vol. 254 No. 3 ISSN: 0304-3940
`Length: 2518 words
`History: Received: July 3, 1998; Revised: August 20, 1998; Accepted: August 20, 1998
`Author: Ryo Saito; Yumiko Suehiro; Hideto Ariumi; Keisuke Migita; Nobuaki Hori; Terusi Hashiguchi; Michinori
`Sakai; Masakazu Saeki; Yukio Takano; Hiro-o Kamiya
`(a)Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka 814–0180,
`Japan
`(b)Department of Pharmacology, Faculty of Dentistry, Kyushu University, Fukuoka 812–0054, Japan
`(c)Hisamitsu Pharmaceutical, Tsukuba 305–0856, Japan
`Body
`ABSTRACT
`We have developed a non-peptide compound, HSP-117, antagonist of the tachykinin NK-1 receptor. Binding of 3H-
`substance P (SP) to the membranes of IM-9 cells was inhibited by the antagonists HSP-117 and CP-99,994, the
`inhibitory activity of HSP-117 being about 50-fold that of CP-99,994. The SP-induced firing responses of single
`neuron activity in slices of the nucleus tractus solitarius of ferrets were inhibited by 10 μM HSP-117.
`Intracerebroventricular injection of HSP-117 significantly inhibited retching and vomiting induced by copper sulphate
`and morphine and the inhibitory effect of HSP-117 on emesis was greater than that of CP-99,994. These results
`indicate that (1) HSP-117 is a potent anti-emetic agent, blocking NK-1 receptors in the nucleus tractus solitarius and
`(2) NK-1 receptors in the nucleus tractus solitarius play an important role in emesis induced by broad-spectrum
`emetic stimuli.
`FULL TEXT
`Substance P (SP) is a family of tachykinin peptides with a variety of pharmacological effects, particularly it plays an
`important role in the transmission of sensory information on noxious stimuli from the periphery to central nervous
`system. Molecular biological and pharmacological studies have demonstrated the existence of three types of
`tachykinin receptor, NK-1, NK-2 and NK-3, which have highest affinities for SP, neurokinin A (NKA) and neurokinin
`B (NKB), respectively, (see reviews 61314).
`6 6.
`C.J. Helke, J.E. Krause, P.W. Mantyh, R. Couture, J. Bannon; Diversity in mammalian tachykinin peptidergic neurons:
`multiple peptides, and regulatory mechanisms; FASEB J.; Vol. 4, (1990), pp. 1606-1615.
`13 13. M. Otsuka, K. Yoshioka; Neurotransmitter functions of mammalian tachykinins; Physiol. Rev.; Vol. 73, (1993), pp. 229-
`308.
`HELSINN EXHIBIT 2056
`Azurity Pharmaceuticals, Inc. v. Helsinn Healthcare S.A.
`IPR2025-00948
`Page 1 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`Recently, NK-1 receptor antagonists were reported to be effective for inhibiting emesis induced by central or
`peripheral emetogens in ferrets 3181920. In addition, binding studies demonstrated that the NK-1 receptor is present
`at high density in the area postrema and the nucleus tractus solitalius, both of which are associated with the emetic
`reflex in ferrets. SP and SP-like immunoreactivity have also been found at significant levels in the area postrema
`and nucleus tractus solitarius of rats and cats 9101112. Moreover, capsaicin or its analog, resiniferatoxin (RTX),
`which are thought to cause depletion of SP, reduce emetic responses, although, their mechanism of action is
`unclear 25. These findings strongly suggest that SP is involved in emetic responses in the central nervous system.
`Recently, our group have developed a non-peptide compound, (2S,3S)-3-[(5-isopropyl-2,3-dihydrobenzofuran-7-yl)
`methyl] amino-2-phenylpiperidine dihydrochloride (HSP-117), as a selective antagonist of the NK-1 receptor (Fig.
`1A). In this study, we examined the effects of this novel NK-1 receptor antagonist on emesis in ferrets, and
`demonstrated the existence of NK-1 receptors in their nucleus tractus solitarius by an electrophysiological
`technique in ferrets.
`Fig. 1. (A) Structure of HSP-117 and (B) inhibitory effects of HSP-117 and CP-99,994 on 3H-substance P binding in
`the IM-9 cell.
`Adult male ferrets (0.6–1.6 kg, Marshall Farms, USA) were housed individually in a room at 20–23°C with a 12:12 h
`light–dark cycle (light on at 0700 h) and were given free access to commercial food and tap water.
`14 14. D. Regoli, D. Drapeau, S. Dion, R. Couture; New selective agonists for neurokinin receptors: pharmacological tools for
`receptor characterization; Trends Pharmacol. Sci.; Vol. 9, (1988), pp. 290-295.
`3 3. C. Bountra, K. Bunce, T.J. Dale, C.J. Gardner, C.C. Jordan, D.J. Twissell, P. Ward; Anti-emetic profile of a non-peptide
`neurokinin NK1 receptor antagonist, CP-99,994, in ferrets; Eur. J. Pharmacol.; Vol. 249, (1993), pp. R3-R4.
`18 18. F.D. Tattersall, W. Rycroft, R.J. Hargreaves, R.G. Hill; The tachykinin NK1 receptor antagonist CP-99,994 attenuates
`cisplatin induced emesis in the ferret; Eur. J. Pharmacol.; Vol. 250, (1993), pp. R5-R6.
`19 19. F.D. Tattersall, W. Rycroft, R.G. Hill, R.J. Hargreaves; Enantioselective inhibition of apomorphine-induced emesis in the
`ferret by the neuokinin1 receptor antagonist CP-99,994; Neuropharmacology; Vol. 33, (1994), pp. 259-260.
`20 20. J.W. Watson, S.F. Gonsalves, A.A. Fossa, S. McLean, T. Seeger, S. Obach, P.L.R. Andrews; The anti-emetic effects of
`CP-99,994 in the ferret and dog: role of the NK1 receptor; Br. J. Pharmacol.; Vol. 115, (1995), pp. 84-94.
`9 9. R.A. Leslie; Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the tractus solitarius,
`area postrema, and dosal motor nucleus of vagus; Neurochem. Int.; Vol. 7, (1985), pp. 191-211.
`10 10. A. Nagashima, Y. Takano, K. Tateishi, Y. Matsuoka, T. Hamaoka, H. Kamiya; Cardiovascular roles of tachykinin peptides
`in the nucleus tractus solitarii of rats; Brain Res.; Vol. 487, (1989), pp. 392-396.
`11 11. A. Nagashima, Y. Takano, K. Tateishi, Y. Matsuoka, T. Hamaoka, H. Kamiya; Central presser actions of neurokinin B:
`increases in neurokinin B contents in discrete nuclei in spontaneous hypertensive rats; Brain Res.; Vol. 499, (1989), pp. 198-
`203.
`12 12. B.W. Newton, B. Maley, H. Traurig; The distribution of substance P, enkephalin and serotonin immunoreactivities in the
`area postrema of the rat and cat; J. Comp. Neurol.; Vol. 234, (1985), pp. 87-104.
`2 2. P.L.R. Andrews, P. Bhandari; Resiniferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in the ferret;
`Neuropharmacology; Vol. 32, No. 8; (1993), pp. 799-806.
`5 5. C. Goso, G. Piovacari, A. Szallasi; Resiniferatoxin-induced loss of vaniloid receptors is reversible in the urinary bladder but
`not in the spinal cord of the rat; Neurosci. Lett.; Vol. 162, (1993), pp. 197-200.
`Page 2 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`Before microinjections into the lateral brain ventricle, ferrets were anesthetized with pentobarbital sodium (40
`mg/kg, i.p.) and placed in a stereotaxic apparatus (Kopf Instruments). A guide cannula (23 gauge stainless steel; 13
`mm length) was inserted into the right lateral brain ventricle (coordination sites: anterial, −2.5 mm; lateral, −3.5 mm
`from the cross-structure). The tip of the guide cannula was located vertically 10 mm below the skull surface and the
`cannula was fixed to the skull with dental cement and two holding screws. After surgery, penicillin (10 000 units
`i.m.) was given as an antibiotic. The ferrets were then allowed to recover for 36–96 h before experiments.
`For experiments on anti-emetic responses, animals were given intracerebroventricularly either HSP-117 or CP-
`99,994, or artificial cerebrospinal fluid (ACSF) as a vehicle control for HSP-117 or saline as a vehicle control for CP-
`99,994, in a volume of 20 μl over a 1 min period. Five minutes later, the animals were given copper sulphate (25.0
`mg/kg intra-gastric) or morphine (0.5 mg/kg s.c.) as a emetogen and the numbers of emetic episodes occurring
`during the following 60 min were recorded. At the end of each experiment, malachite-green dye was injected to
`confirm the site of drug injection.
`Electrophysiological experiments were performed as described previously 7. Ferrets were anesthetized with ether,
`and their brains were quickly removed and placed in cold oxygenated Krebs–Ringer buffer. Coronal slices of the
`brainstem (400 μm thickness) containing each side of nucleus tractus solitarius were cut with a vibratome. The
`slices were allowed to equilibrate in a chamber filled with Krebs–Ringer buffer at 34°C for at least 1.5 h before
`experiments. Then they were transferred to a submerged recording chamber and perfused with Krebs–Ringer
`buffer at a rate of about 3 ml/min at 34°C. The perfused Krebs-Ringer buffer was saturated with 95% O2 and 5%
`CO 2. Drugs were applied by switching the normal perfusing Ringer buffer to a solution containing drug.
`Spontaneous single-unit discharges were recorded with a glass-electrode filled with Ringer's solution (10 MΩ) from
`the nucleus tractus solitarius.
`3H-SP binding was carried out as described previously 17. Human lymphoblasts (IM-9 cells) were grown in RPMI
`1640 culture medium supplemented with 10% fetal calf serum at 37°C under 5% CO2/95% air for a few days and
`then cells harvested by centrifugation at 1500 rpm for 5 min. Pelleted cells were washed by resuspension in 30 ml
`of buffer A (50 mM Tris–HCl pH 7.5, 150 mM NaCl, 0.02% BSA), collected by centrifugation and resuspended in
`assay buffer (buffer A, 40 μg/ml bacitracin, 4 μg/ml leupeptin, 4 μg/ml chymostatin, 4 μg/ml phosphoramidon). Cell
`suspensions (500 μl) at a concentration of 1×107 cells/ml assay buffer were incubated with 3H-SP 10 μl (final 250
`pM) for 60 min at room temperature 1 min after addition of various concentrations of test compounds or non-
`radioactive SP. For removal of unbound 3H-SP, the suspensions were centrifugated at 1500 rpm for 5 min. Then
`the pelleted cells were solubilized in 10 ml of scintillation fluid. Radioactivity in the pellet was determined as the
`specific binding of 3H-SP to the IM-9 cells.
`HSP-117 and CP-99,994 were synthesized at Hisamitsu Pharmaceutical (Tsukuba, Japan). IM-9 cells were
`purchased from the American Type Culture Collection (USA). SP was obtained from Bachem (UK). 3H-SP was
`purchased from Amersham (UK).
`Data are expressed as the mean±SEM for each treatment group. The significance of differences between values for
`vehicle and treatment groups was examined by one-way analysis of variance (ANOVA) followed by Dunnet's test.
`To determine the selectivity of the novel NK-1 antagonist HSP-117, we examined its inhibition and that of CP-
`99,994, and the specific binding of 3H-SP at 2.0 nM to membranes of IM-9 cells. As shown in Fig. 1B, 3H-SP binding
`to the membranes was inhibited by both antagonists, but the inhibitory activity of HSP-117 was more than about 50-
`fold that of CP-99,994.
`7 7. T. Iwase, N. Hori, T. Morioka, D.O. Carpenter; Low power laser irradiation reduces ischemic damage in hippocampal slices
`in vitro; Lasers Surg. Med.; Vol. 19, (1996), pp. 465-470.
`17 17. Y. Takano, A.D. Loewy; 3H-substance P binding in the intermediolateral cell column and striatum of the rat; Brain Res.;
`Vol. 311, (1984), pp. 144-147.
`Page 3 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`Next, we examined the inhibitory effect of HSP-117 on NK-1 receptors by an electrophysiological technique. SP (1
`μM) caused an increase in spontaneous firings in slices of the nucleus tractus solitarius of ferrets. HSP-117 at 10
`μM concentration inhibited the SP-induced firing responses of a single neuron (Fig. 2), although it had no effect on
`the basal spontaneous firing activity.
`Fig. 2. Effects of SP and HSP-117 on spontaneous firing in slices of the brainstem containing nucleus tractus
`solitarius in ferrets. Typical recordings of the firing (upper) and its rate (spikes/s; lower) are shown.
`Oral administration of copper sulphate (25.0 mg/kg, i.g.) or subcutaneous injection of morphine (0.5 mg/kg, s.c.)
`causes retching and vomiting in ferrets. Intracerebroventricular (i.c.v.) injection of HSP-117 (10, 100 μg) dose-
`dependently inhibited the retching and vomiting induced by copper sulphate and morphine (Fig. 3). The inhibitory
`effect of HSP-117 on emesis was greater than that of CP-99,994.
`Fig. 3. Effects of i.c.v. injections of HSP-117 and CP-99,994 on the number of vomits and retches induced by
`copper sulphate (A) and morphine (B). Values are the mean±SEM n=4–6. *P<0.05, **P<0.01 compared with each
`of the controls.
`The physiological roles of SP have been demonstrated and recently the involvements of SP in various clinical
`disorders, such as inflammation, emesis, pain, asthma and cardiovascular disorders have become of interest. In the
`present study, we developed a selective piperidine NK-1 receptor antagonist, HSP-117. Binding experiments
`showed that HSP-117 has about 50-fold of magnitude greater affinity for NK-1 receptors in membranes of IM-9 cells
`than CP-99,994 (Fig. 1B). In IM-9 cells, human NK-1 receptors are predominant and so HSP-117 may be clinically
`useful. Moreover, HSP-117 antagonized the firing responses induced by SP in brain slices of ferrets including the
`nucleus tractus solitarius in vitro (Fig. 2). These findings indicate that HSP-117 is highly selective for NK-1 receptors
`not only in cell membranes but also in organs of the whole body, e.g. the nucleus tractus solitarius, suggesting that
`it should be useful for studies on brain NK-1 receptors.
`In ferrets, emesis is known to be evoked by a wide variety of stimuli 8. There are many reports that systemic
`administration of NK-1 antagonists inhibits emesis 34181920, but there are a few reports on the central effects of NK-1
`antagonists 15. In this study, central injection of HSP-117 (100 μg, i.c.v.) almost completely inhibited emesis
`induced by copper sulphate or morphine and was more effective than the same dose of CP-99,994 (Fig. 3).
`8 8. A.P. Knox, N.L. Strominger, A.H. Battles, D.O. Carpenter; Behavioral studies of sensitivity in the ferret; Brain Res. Bull.; Vol.
`31, (1993), pp. 477-484.
`4 4. C.J. Gardner, D.J. Twissell, J.D. Dale, C.C. Jordan, G.J. Klipatrick, C. Bountra, P. Ward; The broad-spectrum anti-emetic
`activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040; Br. J. Pharmacol.; Vol. 116, (1995), pp. 3158-
`3163.
`15 15. N.M.J. Rupniak, F.D. Tattersall, A.R. Williams, W. Rycroft, E.J. Carlson, M.A. Cascieri, S. Sadowski, E. Ber, J.J. Hale,
`S.G. Mills, M. MacCoss, E. Seward, I. Huscroft, S. Owen, C.J. Swain, R.G. Hill, R.J. Hargreaves; In vitro and in vivo predictors of
`the anti-emetic activity of tachykinin NK1 receptor antagonists; Eur. J. Pharmacol.; Vol. 326, (1997), pp. 201-209.
`Page 4 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`The site of the vomiting center in the brain is of interest. Our results indicate that NK-1 antagonists have a central
`site of action. Moreover, high densities of 3H-SP binding sites have been found in the nucleus tractus solitarius and
`the area postrema of rats 16, although little is known about the distribution of tachykinin peptides in the ferret brain.
`However, the present data do not indicate whether the action of NK-1 receptors in the anti-emetic response is direct
`or involves an other neuronal system, such as serotonergic neurons in the brain, and in fact, SP has been shown to
`be co-localized with serotonin in the peripheral and central nervous systems 1. At present, the mechanisms
`underlying the emetic reflex are not fully understood, but our results suggest that HSP-117 acts within the
`brainstem, and probably within the nucleus tractus solitarius and area postrema.
`Thus, HSP-117 is a high affinity antagonist of the ferret NK-1 receptor, and is the most potent broad-spectrum anti-
`emetic agent known to date. Our study suggests that NK-1 receptors are important for emesis induced by broad-
`spectrum emetic stimuli.
`CONTACT: * Corresponding author. Tel.: +81 92 8716631; fax: +81 92 8630389; e-mail: rsaito@psat.fukuoka-
`u.ac.jp
`References
`6 6. C.J. Helke, J.E. Krause, P.W. Mantyh, R. Couture, J. Bannon; Diversity in mammalian tachykinin peptidergic
`neurons: multiple peptides, and regulatory mechanisms; FASEB J.; Vol. 4, (1990), pp. 1606-1615.
`13 13. M. Otsuka, K. Yoshioka; Neurotransmitter functions of mammalian tachykinins; Physiol. Rev.; Vol. 73,
`(1993), pp. 229-308.
`14 14. D. Regoli, D. Drapeau, S. Dion, R. Couture; New selective agonists for neurokinin receptors:
`pharmacological tools for receptor characterization; Trends Pharmacol. Sci.; Vol. 9, (1988), pp. 290-295.
`3 3. C. Bountra, K. Bunce, T.J. Dale, C.J. Gardner, C.C. Jordan, D.J. Twissell, P. Ward; Anti-emetic profile of a
`non-peptide neurokinin NK1 receptor antagonist, CP-99,994, in ferrets; Eur. J. Pharmacol.; Vol. 249, (1993), pp.
`R3-R4.
`18 18. F.D. Tattersall, W. Rycroft, R.J. Hargreaves, R.G. Hill; The tachykinin NK1 receptor antagonist CP-99,994
`attenuates cisplatin induced emesis in the ferret; Eur. J. Pharmacol.; Vol. 250, (1993), pp. R5-R6.
`19 19. F.D. Tattersall, W. Rycroft, R.G. Hill, R.J. Hargreaves; Enantioselective inhibition of apomorphine-induced
`emesis in the ferret by the neuokinin1 receptor antagonist CP-99,994; Neuropharmacology; Vol. 33, (1994), pp.
`259-260.
`20 20. J.W. Watson, S.F. Gonsalves, A.A. Fossa, S. McLean, T. Seeger, S. Obach, P.L.R. Andrews; The anti-
`emetic effects of CP-99,994 in the ferret and dog: role of the NK1 receptor; Br. J. Pharmacol.; Vol. 115, (1995), pp.
`84-94.
`9 9. R.A. Leslie; Neuroactive substances in the dorsal vagal complex of the medulla oblongata: nucleus of the
`tractus solitarius, area postrema, and dosal motor nucleus of vagus; Neurochem. Int.; Vol. 7, (1985), pp. 191-211.
`16 16. Y. Takano, A. Nagashima, T. Hagio, Y. Nakayama, H. Kamiya; Tachykinin receptor subtype: central cardiovascular
`regulation of tachykinin peptides; Ann. New York Acad. Sci.; Vol. 632, (1991), pp. 476-478.
`1 1. A.H. Amin, T.B.B. Crawford, J.H. Gaddum; The distributions of substance P and 5-hydroxy-tryptamine in the central nervous
`system of the dog; J. Physiol.; Vol. 126, (1954), pp. 596-618.
`Page 5 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`10 10. A. Nagashima, Y. Takano, K. Tateishi, Y. Matsuoka, T. Hamaoka, H. Kamiya; Cardiovascular roles of
`tachykinin peptides in the nucleus tractus solitarii of rats; Brain Res.; Vol. 487, (1989), pp. 392-396.
`11 11. A. Nagashima, Y. Takano, K. Tateishi, Y. Matsuoka, T. Hamaoka, H. Kamiya; Central presser actions of
`neurokinin B: increases in neurokinin B contents in discrete nuclei in spontaneous hypertensive rats; Brain Res.;
`Vol. 499, (1989), pp. 198-203.
`12 12. B.W. Newton, B. Maley, H. Traurig; The distribution of substance P, enkephalin and serotonin
`immunoreactivities in the area postrema of the rat and cat; J. Comp. Neurol.; Vol. 234, (1985), pp. 87-104.
`2 2. P.L.R. Andrews, P. Bhandari; Resiniferatoxin, an ultrapotent capsaicin analogue, has anti-emetic properties in
`the ferret; Neuropharmacology; Vol. 32, No. 8; (1993), pp. 799-806.
`5 5. C. Goso, G. Piovacari, A. Szallasi; Resiniferatoxin-induced loss of vaniloid receptors is reversible in the urinary
`bladder but not in the spinal cord of the rat; Neurosci. Lett.; Vol. 162, (1993), pp. 197-200.
`7 7. T. Iwase, N. Hori, T. Morioka, D.O. Carpenter; Low power laser irradiation reduces ischemic damage in
`hippocampal slices in vitro; Lasers Surg. Med.; Vol. 19, (1996), pp. 465-470.
`17 17. Y. Takano, A.D. Loewy; 3H-substance P binding in the intermediolateral cell column and striatum of the rat;
`Brain Res.; Vol. 311, (1984), pp. 144-147.
`8 8. A.P. Knox, N.L. Strominger, A.H. Battles, D.O. Carpenter; Behavioral studies of sensitivity in the ferret; Brain
`Res. Bull.; Vol. 31, (1993), pp. 477-484.
`4 4. C.J. Gardner, D.J. Twissell, J.D. Dale, C.C. Jordan, G.J. Klipatrick, C. Bountra, P. Ward; The broad-spectrum
`anti-emetic activity of the novel non-peptide tachykinin NK1 receptor antagonist GR203040; Br. J. Pharmacol.; Vol.
`116, (1995), pp. 3158-3163.
`15 15. N.M.J. Rupniak, F.D. Tattersall, A.R. Williams, W. Rycroft, E.J. Carlson, M.A. Cascieri, S. Sadowski, E. Ber,
`J.J. Hale, S.G. Mills, M. MacCoss, E. Seward, I. Huscroft, S. Owen, C.J. Swain, R.G. Hill, R.J. Hargreaves; In vitro
`and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists; Eur. J. Pharmacol.; Vol.
`326, (1997), pp. 201-209.
`16 16. Y. Takano, A. Nagashima, T. Hagio, Y. Nakayama, H. Kamiya; Tachykinin receptor subtype: central
`cardiovascular regulation of tachykinin peptides; Ann. New York Acad. Sci.; Vol. 632, (1991), pp. 476-478.
`1 1. A.H. Amin, T.B.B. Crawford, J.H. Gaddum; The distributions of substance P and 5-hydroxy-tryptamine in the
`central nervous system of the dog; J. Physiol.; Vol. 126, (1954), pp. 596-618.
`Classification
`Language: ENGLISH
`Document Type: Full-length article
`Publication Type: Other (Journal)
`Page 6 of 7
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`Anti-emetic effects of a novel NK-1 receptor antagonist HSP-117 in ferrets
`Journal Code: NSL
`Subject: AMINO ACIDS, PEPTIDES & PROTEINS (90%); MAMMALS (90%); BIOCHEMISTRY (89%);
`NEUROSCIENCE (89%); PHARMACOLOGY (89%); BRAIN (78%); MOLECULAR BIOLOGY (78%); CANCER
`DRUGS (73%); REPORTS, REVIEWS & SECTIONS (73%); CATS (72%); Tachykinins; Emesis; NK-1 antagonists;
`HSP-117; CP-99,994
`Industry: CENTRAL NERVOUS SYSTEM DRUGS (90%); HORMONES, SUBSTITUTES & ANTAGONISTS (90%);
`PHARMACOLOGY (89%); DOPAMINE AGENTS (78%); CANCER DRUGS (73%)
`Load-Date: April 6, 2007
`Neuroscience Letters
`Copyright 1998 Elsevier Science Ireland Ltd All Rights Reserved
`End of Document
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