Co-identity of brain angiotensin converting enzyme with a membrane bound dipeptidyl carboxypeptidase inactivating Met-enkephalin

Benuck, M.; Marks, Neville

doi:10.1016/0006-291x(79)91718-2

Cited by 81 publications

(19 citation statements)

References 16 publications

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“…As the K m is also high (1 mM), the specificity constant (K^JKn) would seem to be unfavorable for metabolism in vivo. 36 However, Benuck and Marks 44 showed with rat brain ACE bound to an immunoaffinity support that the K m of [Met'Jenkephalin was 10-fold lower than with soluble purified human ACE. Other opioid peptides such as 0-neoendorphin and dynorphins are also good substrates of ACE.…”

mentioning

confidence: 99%

Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture.

1990

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confidence: 99%

Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture.

1990

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“…As expected, thiorphan displays a naloxone-reversible analgesia after systemic administration in mice (7). The antinociceptive effect of thiorphan and its ability to prevent in vivo degradation of exogenously administered enkephalins has been widely confirmed recently (11)(12)(13)(14).Nevertheless, the inhibitory potency of thiorphan (Ki = 3.5 nM) is only 40 times stronger against enkephalinase than against angiotensin-converting enzyme [ACE; Ki = 140 nM (7)], a carboxydipeptidase that also displays some ability to split the GlyPhe bond (positions 3 and 4) of enkephalins (15,16). Therefore, given the wide distribution of ACE and its involvement in blood pressure regulation, it is of great importance to develop enkephalinase inhibitors exhibiting both a strong potency and a selectivity as high as possible, in preview of their eventual clinical use.…”

mentioning

confidence: 99%

“…Nevertheless, the inhibitory potency of thiorphan (Ki = 3.5 nM) is only 40 times stronger against enkephalinase than against angiotensin-converting enzyme [ACE; Ki = 140 nM (7)], a carboxydipeptidase that also displays some ability to split the GlyPhe bond (positions 3 and 4) of enkephalins (15,16). Therefore, given the wide distribution of ACE and its involvement in blood pressure regulation, it is of great importance to develop enkephalinase inhibitors exhibiting both a strong potency and a selectivity as high as possible, in preview of their eventual clinical use.…”

mentioning

confidence: 99%

Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan.

Roques¹,

Lucas-Soroca²,

Chaillet³

et al. 1983

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

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Thiorphan, N-[(R,S)-3-mercapto-2-benzylpropanoyliglycine is a highly potent inhibitor (K; = 3.5 nM) of "enkephalinase," a metalloendopeptidase cleaving the Gly-Phe bond (positions 3 and 4) of enkephalins in brain tissue. In accordance with this property, thiorphan displays antinociceptive activity after systemic administration. However, thiorphan also inhibits to a lesser extent (K; = 140 nM) the widely distributed angiotensin-converting enzyme, a carboxydipeptidase implicated in blood pressure regulation. Therefore, in view of an eventual clinical use of enkephalinase inhibitors, it was very important to develop fully specific compounds. Such derivatives were obtained taking into account that N-methylation of the ultimate amide bond of dipeptides strongly decreases enkephalinase affinity without affecting angiotension-converting enzyme recognition, whereas retro-inversion of the amide bond leads to the inverse effect. Thus, the retro-inverso dipeptide (R)-H2N-CH(CH24)-NHCO-CH2-CO2H exhibits an inhibitory potency on enkephalinase (IC50 12 jM) close to that of the natural dipeptide L-Phe-Gly (IC50 3 jIM). This result shows the topological analogy between the crucial components involved in enkephalinase recognition both in active dipeptides and structurally related retro-inverso isomers. Taking into account these observations, retro-thiorphan, (R,S)-HS-CH2-CH-(CH20)-NHCO-CH2-COOH, was prepared. As compared to thiorphan, the retro isomer is 50% as potent (Ki = 6 nM) on enkephalinase but displays a drastic loss of potency on angiotension-converting enzyme (IC50 > 10,000 nM). This specificity was interpreted as a consequence of differences in the stereochemical constraints involving enzyme-inhibitor hydrogen bonding. This hypothesis is supported by reported crystallographic studies on related enzymes such as thermolysin and carboxypeptidase A. As expected, retro-thiorphan exhibits about the same analgesic potency as thiorphan on the hot plate and writhing tests in mice. Therefore, the topological concept of retro-inverso isomers could be extended to other enkephalinase inhibitors, allowing the design of potent and highly selective compounds occurring as new classes of analgesic and psychoactive agents.An important approach in the search for antinociceptive agents is to prevent degradation of the endogenous morphine-like peptides, enkephalins (1, 2), at the synaptic level. The characterization of a membrane.bound metalloendopeptidase called enkephalinase (3)(4)(5), which seems to be specifically involved in cleavage of the Gly-Phe (positions 3 and 4) bond of [Met]enkephalin (Tyr-Gly-Gly-Phe-Met) or [Leu]enkephalin (Tyr-GlyGly-Phe-Leu), made this approach possible. A highly potent enkephalinase inhibitor, thiorphan, N-[(R,S)-3-mercapto-2-benzylpropanoyl]glycine [Ki = 3.5 nM (6, 7)], was rationally designed taking into account the occurrence in this peptidase of (i) a Zn atom in its catalytic site able to coordinate a thiol group with a strong affinity (7, 8); (ii) a Sj' subsite exhibiting a specificity for aro...

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“…Given that the degradation of systemic enkephalin is believed to be by the action of a dipeptidyl dipeptidase associated with vascular endothelial tissue (Erdos et al, 1978;Benuck & Marks, 1979) were given (10, 20, 40, and 80 tig kg-I each in 0.1 ml) in a randomized manner at 10 min intervals. Each animal then received either captopril (2 mg kg-1, i.v.)…”

Section: Introductionmentioning

confidence: 99%

Captopril potentiates the vasodepressor action of Met‐enkephalin in the anaesthetized rat

Nicolantonio¹,

Hutchinson²,

Takata³

et al. 1983

British J Pharmacology

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Co-identity of brain angiotensin converting enzyme with a membrane bound dipeptidyl carboxypeptidase inactivating Met-enkephalin

Cited by 81 publications

References 16 publications

Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture.

Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture.

Complete differentiation between enkephalinase and angiotensin-converting enzyme inhibition by retro-thiorphan.

Captopril potentiates the vasodepressor action of Met‐enkephalin in the anaesthetized rat

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