Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes

Fournié‐Zaluski, Marie‐Claude; Chaillet, Pierre; Bouboutou, Romaine; Coulaud, Annie; Cherot, Patrick; Waksman, Gilles; Costentin, Jean; Roques, Bernárd P.

doi:10.1016/0014-2999(84)90575-2

Cited by 164 publications

(51 citation statements)

References 10 publications

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“…Therefore to achieve a better understanding of the physiological role of nociceptin/orphanin FQ, selective inhibitors of the heptadecapeptide metabolism were co-administered. In contrast to NEP/APN inhibitors, which have an intrinsic opioidergic action [22], aminopeptidase and endopeptidase 24.15 inhibitors alone, or in association, did not induce pharmacological effects after central administration, indicating that there is little or no tonic participation of endogenous nociceptin/orphanin FQ in the behaviours measured (Figs. 2 and 3).…”

Section: Resultsmentioning

confidence: 79%

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Noble

Roques

1997

FEBS Letters

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The behavioral effects induced by central administration in mice of the endogenous ORLj (opioid receptor-like]) ligand, nociceptin/orphanin FQ, were investigated in the absence or presence of inhibitors of aminopeptidase N (bestatin) and endopeptidase 24.15 (Z-(L!D) PheT(P0 2 CH 2 )(L,D)Ala-Arg-Phe) recently shown to be involved in the metabolism of the heptadecapeptide in vitro. A severe reduction in motor activity induced by nociceptin/orphanin FQ was measured in two tests (spontaneous motor activity and open field). This pharmacological effect was shown to be potentiated by the association of bestatin and Z-(LiD )PheT(P0 2 CH2)(L,D)Ala-Arg-Phe, confirming in vivo the involvement of these peptidases in nociceptin/ orphanin FQ inactivation. In our conditions, these inhibitors were devoid of intrinsic effects, suggesting a low tonic regulation by the heptadecapeptide of the measured behaviour.

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Section: Resultsmentioning

confidence: 79%

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Noble

Roques

1997

FEBS Letters

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“…Values are the mean of two independent determinations and represent the radioactivity content of each peak expressed as a percentage of total radioactivity recovered after HPLC. Inhibitor concentrations were as in Table 3 Inhibitor Radioactivity in neurotensin degradation products 11 inhibitor, kelatorphan [32], fully inhibited the formation of neurotensin-(I -11) (by about 84% of control value) (not shown) confirmed the involvement of this peptidase in the cleavage at the Tyrl'-Ile'' site of neurotensin. The specific proline endopeptidase inhibitor, Z-Pro-prolinal [25] totally inhibited the formation of neurotensin-(1 -7) generated by circular muscle plasma membranes (Table 3).…”

Section: Inhibitormentioning

confidence: 81%

Peptidases in dog-ileum circular and longitudinal smooth-muscle plasma membranes. Their relative contribution to the metabolism of neurotensin

et al. 1987

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We established the content in neuropeptide-metabolizing peptidases present in highly purified plasma membranes prepared from the circular and longitudinal muscles of dog ileum. Activities were measured by the use of fluorigenic substrates and the identities of enzymes were confirmed by the use of specific peptidase inhibitors. Endopeptidase 24.1 1, angiotensin-converting enzyme, post-proline dipeptidyl aminopeptidase and aminopeptidases were found in both membrane preparations. Proline endopeptidase was only detected in circular smooth muscle plasma membranes while pyroglutamyl-peptide hydrolase was not observed in either tissue. The relative contribution of these peptidases to the inactivation of neurotensin was assessed. The enzymes involved in the primary inactivating cleavages occurring on the neurotensin molecule were as follows. (1) In both membrane preparations, endopeptidase 24.1 1 was responsible for the formation of neurotensin-(1 -11) and contributed to the formation of neurotensin-( 1 -10) ; a recently purified neurotensin-degrading neutral metallopeptidase was also involved in the formation of neurotensin-(I -10). (2) A carboxypeptidase-like activity hydrolysed neurotensin at the Ile1'-Leu13 peptide bond, leading to the formation of neurotensin-(I -12). (3) Proline endopeptidase and endopeptidase 24.15 only occurred in circular muscle plasma membranes, yielding neurotensin-(I -7) and neurotensin-(I -8), respectively. In addition, the secondary processing of neurotensin degradation products was catalyzed by the following peptidases. (1) In circular and longitudinal muscle membranes, angiotensin-converting enzyme converted neurotensin-(I -10) into neurotensin-(I -8) and tyrosine resulted from the rapid hydrolysis of neurotensin-(I 1 -13) by bestatin-sensitive aminopeptidases. (2) A post-proline dipeptidyl aminopeptidase activity converted neurotensin-(9-13) into neurotensin-(11 -13) in circular muscle plasma membranes. The mechanism of neurotensin inactivation occurring in these membranes will be compared to that previously established for membranes from central origin.Neurotensin is a 13-amino-acid peptide (Glp-Leu-TyrGlu-Asn-Lys-Pro-Arg-Arg-Pro-Tyr-Ile-Leu) first isolated from hypothalami [l] and later from the intestine of bovine [2]. In the periphery, neurotensin-like immunoreactivity was reported to be essentially distributed in the jejunum and in the distal part of small intestine of several mammalian species [3,4]. Immunofluorescence studies showed that neurotensin was mainly located in discrete cells of the mucosa corresponding to the lower portion of dog ileum [5]. In addition to these studies, specific neurotensin receptors were

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“…This result has been confirmed in vivo. Thus, because of the complementary role of NEP and APN in enkephalin inactivation, selective inhibition of only one of these peptidases gives weak antinociceptive responses whereas strong analgesic effects can be obtained after complete inhibition of opioid peptide metabolism with combination of selective inhibitors (5). This leads us to propose the concept of ''dual'' inhibitors.…”

mentioning

confidence: 99%

“…This leads us to propose the concept of ''dual'' inhibitors. Accordingly, compounds able to interact with the SЈ 1 and SЈ 2 subsites of NEP and APN, such as kelatorphan (5,6) and RB 38A (7), were shown to produce strong analgesic responses caused by a large increase in the extracellular levels of enkephalins (4). However, these compounds ( Fig.…”

mentioning

confidence: 99%

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

Chen

Noble

Coric

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

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Inhibition of aminopeptidase N and neutral endopeptidase-24.11, two zinc metallopeptidases involved in the inactivation of the opioid peptides enkephalins, produces potent physiological analgesic responses, without major sideeffects, in all animal models of pain in which morphine is active. Dual inhibitors of both enzymes could fill the gap between opioid analgesics and antalgics. Until now, attempts to find a compound with high affinity both for neutral endopeptidase and aminopeptidase N have failed. We report here the design of dual competitive inhibitors of both enzymes with K I values in the nanomolar range. These have been obtained by selecting R 1 , R 2, and R 3 determinants in aminophosphinic-containing inhibitors: NH 2 OCH(R 1 )P(O)O (OH)CH 2 OCH(R 2 )CONHOCH(R 3 )COOH, for optimal recognition of the two enkephalin inactivating enzymes, whose active site peculiarities, determined by site-directed mutagenesis, have been taken into account. The best inhibitors were 10؋ more potent than described dual inhibitors in alleviating acute and inf lammatory nociceptive stimuli in mice, thus providing a basis for the development of a family of analgesics devoid of opioid side effects.Acute and chronic pain are incapacitating diseases, and an improvement in their management is a high priority. Two classes of pain-alleviating substances currently are used in clinic. The first one is constituted by morphine and surrogates, which are the most potent and useful compounds to reduce severe pain, including pain associated with terminal issues. Antalgics including aspirin, paracetamol, and related substances provide the second group. These compounds inhibit the formation of hyperalgesic substances such as prostaglandins and are efficient in reducing inflammatory pain. However, there is a need for compounds capable of filling the gap between opioids and antalgics, which could be used for the treatment of postoperative, osteoarticular, and neuropathic pain as well as pain in children and in the elderly.One of the most promising avenues in the search for such compounds is to improve the potency of the physiological system of pain control (1), constituted by the endogenous opioid peptides, enkephalins which interact with two specific binding sites, the and the ␦ receptors, strategically located at various levels of nociceptive pathways (2). This can be realized by inhibition of the membrane-bound zinc metallopeptidases involved in the rapid inactivation of the enkephalins. One of these enzymes is neutral endopeptidase-24.11 (NEP, neprilysin, EC 3.4.24.11) and other one is an exopeptidase, aminopeptidase N (APN, EC 3.4.11.2). Biological studies performed on rat brain and spinal cord slices (3, 4) have shown that thiorphan, a selective NEP inhibitor, or bestatin, an APN inhibitor, did not significantly prevent [ 3 H]Met-enkephalin catabolism whereas their combination resulted in a clear reduction of the peptide degradation. This result has been confirmed in vivo. Thus, because of the complementary role of NEP and APN in e...

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Analgesic effects of kelatorphan, a new highly potent inhibitor of multiple enkephalin degrading enzymes

Cited by 164 publications

References 10 publications

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Association of aminopeptidase N and endopeptidase 24.15 inhibitors potentiate behavioral effects mediated by nociceptin/orphanin FQ in mice

Peptidases in dog-ileum circular and longitudinal smooth-muscle plasma membranes. Their relative contribution to the metabolism of neurotensin

Aminophosphinic inhibitors as transition state analogues of enkephalin-degrading enzymes: A class of central analgesics

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