Analgesic and acute central nervous system side effects of the intravenously administered enkephalinase inhibitor SCH 32615 (original) (raw)
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Neuropharmacology, 2001
The aim of this study was to investigate the facilitatory effects of subanalgesic or low doses of different drugs (acetylsalicylic acid, ibuprofen and morphine) on the antinociceptive responses induced by the endogenous opioid peptides, enkephalins, protected from their catabolism by the dual enkephalin-degrading enzymes inhibitor RB101. According to the analgesic profile of the three studied compounds different antinociceptive assays were used: the hot plate and formalin tests in mice, and the tail flick and paw pressure tests on inflamed paws in rats and polyarthritic rats. Facilitatory effects of subanalgesic doses of acetylsalicylic acid and ibuprofen on RB101-induced antinociceptive responses were observed in the early and late phases of the formalin test, respectively. In the hot plate, tail flick and paw pressure tests, the dose-dependent analgesic effects of RB101 were strongly potentiated by subanalgesic doses of morphine (0.5 mg/kg), while in these tests, acetylsalicylic acid and ibuprofen were unable to modify the RB101-induced antinociceptive responses. The synergism in antinociceptive effects observed with the combination of RB101 and morphine supported by isobolographic analysis, may have interesting clinical implications, considering both the lack of opiate drawbacks observed with RB101 and the high potentiation of its antinociceptive effects with very low doses of morphine.
Antagonism of stress-induced analgesia by D-phenylalanine, an anti-enkephalinase
Pharmacology Biochemistry and Behavior, 1980
Methionine- and leucine-enkephalin produce mild and transient analgesic effects, presumably because of enzymatic degradation. Administration of high (250 mg/kg) doses of D-phenylalanine retards the degradation process and elicits analgesia which is reversed by naloxone and which summates with electroacupuncture analgesia. The present study evaluated D-phenylalanine's dose-dependent effects upon a non-opioid analgesic treatment, cold-water swims (CWS), and compared this with morphine. following determination of flinch-jump baselines, three groups of rats received respectively either 25, 50 or 100 mg/kg of D-phenylalanine intraperitoneally in three conditions: alone, with CWS (2 degrees C for 3.5 min), and with morphine (5 mg/kg, SC). Parallel controls with saline were also tested. Simultaneous exposure with each minimally analgesic dose of D-phenylalanine reduced significantly the analgesic, but not hypothermic effects of CWS. By contrast, morphine analgesia was unaffected by D-phenylalanine. These data provide further support that different pain-inhibitory systems mediate CWS and morphine analgesia and suggest that activation of one system is capable of exerting collateral inhibition upon the other.
Novel approaches in the development of new analgesics
Neurophysiologie Clinique/Clinical Neurophysiology, 1990
A recently developed series of highly selective and systemically active g-agonists such as Tyr-X~Gly-Pfie~Letl~Thr(OtBu), with X = D.Ser (OtBu) in BUBU and X = D.Cys(StBu) in BUBUC~ and complete ifihibitors of enkeptmlin metabolism (Kelatorphan, RB 38 A, PC 12) have enabled the major role played by/z-opioid receptors in supraspinal analgesia to be demonstrated• This is in agreement With the~results of in vivo ~t-receptor.~occupancy measured by taking into account the cross-reactivity of the ~-lig~md~. for ~,-sites,.In contrast(# and 3 binding sites seem to act independently to control pain at th~ spinal level. S~rong.anai'gesic effects, especially in arthritic rats, can also be obtained by complete protection of toni-cally~or tplra~gmall~¢ released endogenous enkephalins with mixed inhibitors such as RB38A. Chronic icv • ¢ , administration of tll~t agomst,DAGO, led to a severe naloxone precipitated withdrawal syndrome whilst a weak dependence was seen with the g agonist, DSTBULET or with RB 38 A. Moi-eo~vev;rmi~d.,inhibi'tors did not induce any significant respiratory depression• All these data emphasize the iriterest ink'de-vel6pping~--agonis,l~s,and mixed inhibitors with appropriate biovailability for clinical evaldati0m analgesics / pain R~suml~-'---D~veloppement r~cent d'une nouvelle s~rie d'agonistes opioides, ,Le ddveloppement r~cent d'une nouvellb s~rie d'agonistes opioi'des ~ hautement sdlectifs et actifs par voie ayst~mique te'ts tlue Tyr-X-Gly-Phe-Leu= Thr(OtB~):avec X = D. Ser(OtBu) B UB U et x = D. Cys(StBu) B UBUC,/ainsi que d " une nou velle. sd/ie d'fiihibiteurs complets du mdtabolisme des enkdphdines (k~latorphan, RB 38A., PC 12) a permis de'dd}nontrer l'implication majoritaire des rdcepteurs tz clans l'analgdsie supraspinale. Ceci est e~ ae¢ord avec les expdriences,in vivo d'occupation des sites tz, lorsque l'on prend en compte la:rdaetivit~ eroisde des,ligands~ pou~les sites ~z. Inversement les sites de liaison tt et ~ semblek~t modulds ind~pendamment lg contr~le'de;douleur au niveau spinal. De plus, l'utilisation d'inhibiteurs tel tlRe le RB 384, qui protbgent compldtement~:les enkdphtffines endog~nes libdrdes de fa~on tonique,et'plrasique de la ddgradation enzymatique, conduit d des eff~ts analgdsiques intenses, en particulier chez le rat arthitique.: Une administration chronique~par voie icy de DAGO, un agoniste ~z sdlectif,-suivie;d'une administrationde naldxone; induit un sysdrome de, manctu, e sdvbre, analogue d celui induit par la morphine, alors qu'un effet de ddpendclnce fait~esrob,~ervd avec le DSTBULET ou le RB 38A. Par ailleurs, les inhibiteurs mixtes n'induisent pfts de ddpression respiratoire. Toutes ces donndes ddmontrent l'int~r~t "de d~velopper des agonistes ~et des inhibiteurs mixles prdsentant la biodisponibilitd ndcessaire pour une ~valuation clinique. analgdsique ,/ douleur
Journal of Medicinal Chemistry, 1992
The cyclic peptide [2,6-dimethyl-Tyr1,~Penz,~Pen6]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyrl residue of [~P e n~p P e n~] e n k e p h a l i n (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the S opioid receptor and a 35-fold increase in potency at the p receptor while substantial S receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 waa inactive following systemic administration of doses as high aa 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an EDw of 2.6 mg/kg. Thew resulfe demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyrl with DMT.
Pain, 1997
RB 101 (N-((R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopropyl)-l-phenylalanine benzyl ester) is a full inhibitor of the enkephalin-catabolizing enzymes, which induces strong naloxone-reversible antinociceptive responses after i.v. or i.p. administration, but is only slightly active after oral administration. Chemical modifications were introduced on this compound, resulting in molecules such as RB 120 (N-((S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyldithio]-1-oxopropyl)-l-alanine benzyl ester), which was selected for a complete study, after oral administration, in various assays commonly used to select analgesics: mouse hot plate test, rat tail-flick test, electrical stimulation of the tail in rats, paw pressure test on inflamed paws in rats, acetic acid-induced writhing test and the formalin test in mice. RB 120 induced potent dose-dependent antinociceptive responses in all these tests after oral administration. The differences in antinociceptive effects induced by RB 120 in the various assays is probably related to the amount of enkephalins released and to the efficiency of peptidase inactivation in particular brain regions implicated in the control of a given nociceptive input. The goal of discovering orally active analgesics endowed with a potency similar to that of morphine but devoid of its major side-effects, seems now to have been reached with mixed neutral endopeptidase/aminopeptidase N (NEP/APN) inhibitors, although these compounds have yet to be evaluated in clinical trials. © 1997 International Association for the Study of Pain. Published by Elsevier Science B.V.
Anesthesia & Analgesia, 1998
2.1. Preparation of liposome formulations Structurally multilamellar liposomes were prepared from dipalmitoyl phosphatidyl choline (DPPC)-cholesterol in 50% ratio using the dry-film hydration by vortex mixer Background/aim: Based on our previous in vitro study with multilamellar liposomal bupivacaine (MLB) versus bupivacaine alone in artificial cerebrospinal fluid, we aimed to investigate in vivo antinociceptive effect of intrathecal MLB by determining tail flick latency (TFL) time after thermal stimulation in rats. Materials and methods: After preparing MLB and high-yield drug entrapment in liposome (HYDEL) bupivacaine, 18 female Wistar rats were assigned to 3 groups as control (bupivacaine) and study groups (MLB and HYDEL bupivacaine) including 6 rats in each group to administer these drugs intrathecally. Antinociceptive activity was determined in terms of TFL time after thermal stimulation. Maximum possible effect (MPE) calculated from TFL times and rats with motor block were documented. Results: TFL times after intrathecal injection of HYDEL bupivacaine were significantly longer than that of the control and MLB groups (P < 0.05) and returned to baseline 180 min after intrathecal injection. MPE (100%) with intrathecal HYDEL bupivacaine occurred between 10 to 45 min. Afterwards, MPEs were 70% and 50% for the control and MLB groups, respectively. Motor block disappeared after 20 min in the study groups while it lasted 75 min in the control. Conclusion: Intrathecal administration of MLB and HYDEL bupivacaine in rats resulted in longer duration of antinociceptive activity with shorter motor block duration.
Antinociceptive activity of glycosidic enkephalin analogues
Psychopharmacology, 1990
The antinociceptive activity of two new enkephalin analogues: N l5-(/%D-glucopyranosyl)[D-Met2, ProS]enkephalinamide and N~'5-(/~-D-galactopyranosyl)[D-Met 2, ProS]enkephalinamide was assessed using the tail immersion and paw pressure behavioural tests. Both enkephalin analogues appear to be more active than morphine when injected either into the fourth ventricle or intrathecally; the galactose analogue is more than 5000 times more active than morphine when injected into the fourth ventricle. The analgesic effects produced by the analogues are partially reversed by SC naloxone (0.1 mg/kg) and totally reversed when the dose of naloxone used was 1 mg/kg, suggesting that the analogues act upon more than one type of opiate receptor Key words: Enkephalin analogues-Analgesia-Fourth ventricle-Intrathecal-Tail immersion-Paw pressure chemical nature of opiate receptors have yielded increasing evidence of its glycolipid nature (Gioannini et al. 1984, Cho et al. 1986). Thus it seemed worthwhile to check how the introduction of a glycosidic moiety in an enkephalin analogue may affect the opioid potency of the parent compound.
Anesthesia & Analgesia, 2007
Contulakin-G is a novel conopeptide with an incompletely defined mechanism of action. To assess nociceptive activity we delivered Contulakin-G as a bolus intrathecally (0.03, 0.1, 0.3, 3 nmol) or epidurally (10, 30, 89 nmol) in rats. Intrathecal Contulakin G significantly decreased Phase II and, to a lesser degree, Phase I paw flinching produced by intradermal formalin. Intrathecal and epidural doses of ED50s were 0.07 nmol and 45 nmol, respectively, giving an epidural/intrathecal ED 50 ratio ϭ 647). In dogs, intrathecal Contulakin-G (50-500 nmoL) produced a dose-dependent increase in the thermally evoked skin twitch latency by 30 min after administration, as did morphine (150 and 450 nmol). Epidural morphine (750 and 7500 nmol), but not epidural 1000 nmol Contulakin-G, also significantly decreased skin twitch in dogs. No changes in motor function were seen in any rats or dogs receiving these doses of Contulakin-G. In dogs, no physiologically significant dose-dependent changes in motor function, heart rate, arterial blood pressure, or body temperature were found. Contulakin-G is a potent antinociceptive drug when delivered intrathecally with no observable negative side effects in rats or dogs and may provide an alternative to opioid spinal analgesics.
Pharmacology research & perspectives, 2015
The peripheral endogenous opioid system is critically involved in neuropathic and inflammatory pain generation as suggested by the modulation of opioid receptors expression and enkephalins (ENKs) release observed in these painful conditions. Accordingly, an innovative approach in the treatment of these nocifensive events is to increase and maintain high local concentrations of extracellular pain-evoked ENKs, by preventing their physiological enzymatic inactivation by two Zn metallopeptidases, the neutral endopeptidase (NEP, neprilysin, EC 3.4.24.11) and the neutral aminopeptidase (APN, EC 3.4.11.2). With this aim, new orally active dual ENKephalinase inhibitors (DENKIs) were designed as soluble prodrugs by introducing a N-terminal cleavable carbamate in the previously described aminophosphinic inhibitors. This induces long-lasting antinociceptive responses after oral administration, in various rodent models of inflammatory and neuropathic pain. These responses are mediated through s...