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Antinociceptive and Antidepressant-Like Profiles of BL-2401, a Novel Enkephalinase Inhibitor, in Mice and Rats

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Antinociceptive and Antidepressant-Like Profiles of BL-2401, a Novel Enkephalinase Inhibitor, in Mice and Rats Antinociceptive and Antidepressant-Like Profiles of BL-2401, a Novel Enkephalinase Inhibitor, in Mice and Rats Atsuko Kita1, Kiyomi Imano1, Yasuhiro Seto1, Ikuhisa Yakuo2, Takashi Deguchi3 and Hideo Nakamura4 1 Department of Pharmacology I, Discovery Research Laboratories I, 2Department of Toxicology and Pharmacology, Developmental Research Laboratories,3Department of Chemistry II, Discovery Research Laboratories II, Dainippon Pharmaceuticalof Drug RegulatoryCo., Ltd., 33-94 Affairs, Enoki, Suita/Osaka 564, Japan4Division Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki, Suita/Osaka 564, Japan Received May 26, 1997 Accepted August 29, 1997 ABSTRACT-To clarify the properties of BL-2401 ((•})-3-[2-benzyl-3-(propionylthio) propionyl]amino-5 methylbenzoic acid), a novel enkephalinase inhibitor, we examined its antinociceptive and antidepressant like activities after oral administration, along with their association with endogenous opioid systems. BL 2401 produced an antinociceptive effect after oral administration in the mouse phenylbenzoquinone writh ing test (ED50: 12.4 mg/kg) and the rat acetic acid writhing test (ED50: 55.8 mg/kg), the antinociceptive effect being antagonized by naloxone hydrochloride. BL-2401 also relieved arthritis-induced hyperalgesia in rats. In the mouse hot-plate and tail pressure tests, BL-2401 showed significant but modest antinociception at higher doses (200 and 400 mg/kg). In addition, BL-2401 (100 mg/kg) produced a naloxone-reversible antidepressant-like effect in the mouse forced swimming test. As for the mechanism of the action, the active metabolite of BL-2401, BL-2240 ((•})-3-(2-benzyl-3-mercaptopropionyl) amino-5-methylbenzoic acid), selectively inhibited enkephalinase in vitro (IC50: 5.2 nM). Oral administration of BL-2401 to mice sig nificantly inhibited the enkephalinase activity in the striatum and also potentiated the antinociceptive effect of (D-A1a2,Met5)-enkephalin given intracisternally. These findings indicate that BL-2401 is an orally active enkephalinase inhibitor and may produce antinociceptive and antidepressant-like effects in association with endogenous opioid systems. Keywords: BL-2401, Enkephalinase inhibitor, Antinociception, Antidepressant-like action, Opioid The discovery of enkephalins in 1975 (1) accelerated the opioid receptors. Moreover, enkephalinase inhibitors and research on endogenous opioid systems, leading to suc exogenous enkephalins have been reported to relieve cessive isolation of various opioid peptides and fruitful forced swimming-induced immobility and conditioned investigation of their physiological, pathological and suppression of motility (9-12), supporting the physio pharmacological roles (2, 3). More recently, several logical roles of endogenous enkephalins in stress groups have succeeded in molecular cloning of a-, B response, mood or emotion. Various enkephalinase in and x-opioid receptors (4). These findings have been stimu hibitors have been reported in the literature (6), and they lating the development of novel analgesics acting via show characteristic profiles; e.g., thiorphan, the proto endogenous opioid systems, which has progressed along type of enkephalinase inhibitor, produces an antinoci two strategies: first, direct ligands to opioid receptors, ceptive effect after i.v. and i.c.v. administration (13). such as selective x-opioid receptor agonists (5), and sec Acetorphan, a prodrug of thiorphan, shows antinocicep ond, modulators of endogenous opioids, such as enkepha tive and antidepressant-like effects after i.v. administra linase inhibitors (6). tion (11). In addition, RB101 (N-[(R,S)-2-benzyl-3[(S)(2 Enkephalinase (neutral endopeptidase, EC. 3.4.24.11), amino-4-methylthio)butyl dithio]-1-oxopropyl]-L-phenyl as well as aminopeptidase, has been shown to play an alanine benzyl ester) produces potent antinociceptive and important role in degrading enkephalins in vivo (7). The antidepressant-like effects through its activity to inhibit inhibitors of enkephalinase have been expected to have both enkephalinase and aminopeptidase (12, 14). an antinociceptive effect (6, 8), but not to elicit morphine However, few compounds have been demonstrated to like side effects because they do not bind directly to show an antinociceptive effect after oral administration; that is, SCH34826 ((S)-N-[N-[1-[[(2,2-dimethyl-l,3 according to the method of Ueda et al. (22). dioxolan-4y1) methoxy]carbonyl]-2-phenylethyl]-L-phenyl Acetic acid writhing test in rats (20, 23): Male Wistar alanine]-,3-alanine) (15) and ONO9902 (16). rats (90-130 g) were used. Writhing was induced by i.p. We have aimed to develop an orally active enkepha injection of 1 ml of 1 % aqueous acetic acid. Rats showing linase inhibitor as an analgesic drug that does not cause writhing responses within 15 min after the acetic acid in morphine-like side effects such as drug dependency (17). A jection were used for the experiment. BL-2401 and other novel compound, BL-2240 ((±)-3-(2-benzyl-3-mercapto test drugs were orally administered 15 min after the acetic propionyl) amino-5-methylbenzoic acid), was found to acid injection, and the number of writhes was counted for inhibit enkephalinase potently, and its prodrug, BL-2401 a 20-min period commencing 45 min after the oral ad ((±)-3-[2-benzyl-3-(propionylthio) propionyl]amino-5 ministration (1 hr after acetic acid injection). The anti methylbenzoic acid), was synthesized as an orally active writhing ED50 was calculated from the effective rates as antinociceptive compound. BL-2401 was metabolized to BL cited above. 2240; a pharmacokinetic study demonstrated that BL-2240 Tail pressure test in mice (20): Male ddY mice (22-30 was detected in the plasma and brain of mice and rats g) were used. The root of the tail was gradually pressed after oral administration of BL-2401 (K. Hayashi and with the apparatus of Nakamura and Shimizu (24). The M. Miyamoto, unpublished data). Thus, the present study pressure to elicit biting behavior was measured as a pain was carried out to characterize the antinociceptive profile index (1 mm =12.5 g) at 30-min intervals for 3 hr after of BL-2401 in comparison with codeine and aspirin. We oral administration of BL-2401 or other test drugs. The also investigated its antidepressant-like effect that might pressure was not over 50 mm to avoid injury. In the be of benefit for relief of pain; patients with pain often Results section, the scale of the pressure threshold was have depressive disorders (18). In addition, the potency represented by g. of BL-2401 in inhibiting enkephalinase was evaluated Hot plate test in mice (15, 25): Male ddY mice (20-26 using in vitro, ex vivo and in vivo assays to ascertain the g) were treated with BL-2401 or other test drugs 30 min mechanism of its effects. before testing. The mouse was put onto a heated surface (501C), and the latencies of the paw licking and the jump MATERIALS AND METHODS were measured. A plastic cylinder (20-cm-high and 15 cm in diameter) was used to keep the mouse on the heated Animals plate. Cut-off time was set at 400 sec. ddY Mice and Wistar rats were purchased from Japan Paw pressure test in adjuvant-induced arthritic rats: SLC (Hamamatsu) and SD rats from Clea Japan (Osaka). A 10 mg/ml suspension of adjuvant (Mycobacterium Animals were housed in groups (except for arthritis test) butyricum; Difco, Detroit, MI, USA) was prepared using under conditions of controlled temperature (23±21C), light mineral oil (Bayol F). A 0.06 ml volume of this sus humidity (55-L10%) and light (06:00-18:00 hr). Food pension was injected intradermally into the root of the and water were available ad libitum. Each animal was tail of female SD rats (8-weeks-old). Two weeks later (day used only once in all experiments. 14), rats showing arthritis in their hind paws were select ed, and they were orally administered BL-2401 or codeine Nociceptive tests phosphate once a day during the following 7 days (days Phenylbenzoquinone writhing test in mice (19, 20): 14-20). The nociceptive threshold of the hind paw for Female ddY mice (18-22 g) were used. Writhing was mechanical stimulation was measured with the apparatus induced by i.p. injection of 10 ml/kg of 0.03% phenyl cited in the section on the tail pressure test, and the pres p-benzoquinone in a 5% ethanol aqueous solution. The sure to elicit either a struggle response or paw withdrawal number of writhes was counted for a 15-min period com was determined. The cut-off pressure was 50 mm. The mencing 5 min after the phenylbenzoquinone injection. pressure test was done before and 1 hr after drug ad When the writhes were 50% or less the mean number in ministration on day 14 and at 1 hr after drug administra the vehicle control group, the dose was considered effec tion on days 16, 18 and 20. On days 21 and 28 (1 and 8 tive. The anti-writhing ED50 and 95076 confidence limits days after the last administration), only the pressure test were calculated from the effective rates (% of number of was done. In the Results section, the scale of the pressure mice in which the dose was effective/number of mice test threshold was represented by g. ed) according to the method of Litchfield and Wilcoxon (21). BL-2401 and other test drugs were orally admin Antidepressant tests istered 30 min before the injection of phenylbenzoqui Forced-swimming test in mice (26): Male ddY mice none. Intracisternal (i.c.) administration of naloxone (25 32 g) were dropped into a vertical cylinder contain hydrochloride was performed in a volume of 10 p1/mouse ing 15 cm of water at 21-231C and left there for 6 min. The total duration of immobility during the last 4 min clude blood from the brain. The striata were dissected and was measured. Mice were treated orally with BL-2401 1 hr homogenized with 1 ml of 50 mM Tris-HCl buffer (pH before the test.
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