Cyclic somatostatin analogues as potent antagonists at μ-, but not δ- and κ-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain

Arie H. Mulder, George Wardeh, François Hogenboom, Wieslaw Kazmierski, Victor J Hruby, Anton N M Schoffelmeer

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Abstract

The opioid receptor antagonist properties of four conformaiionally constrained cyclic octapeptidc analogues of somatostatin were investigated using in vitro functional paradigms of μ-, δ- and κ-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pcn-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of μ-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMc)Phc-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenalinc (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of κ-opioid receptors by the cyclohcxylbenzeneacctamidc U69593 (0.02 μM) inhibited (by 40-45%) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of δ-opioid receptors by [D-Scr2O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 μM) caused an inhibition (by 38-46%) of striatal [14C]acctylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 μM DAGO on cortical [3H]NA release. Thus, the cyclic octapcptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the μ-opioid receptors mediating presynaptic inhibition of NA release in the brain. The μ-rceeptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.

Original languageEnglish (US)
Pages (from-to)1-6
Number of pages6
JournalEuropean Journal of Pharmacology
Volume205
Issue number1
DOIs
StatePublished - Nov 19 1991

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Tics
Opioid Receptors
Somatostatin
Neurotransmitter Agents
Brain
Ala(2)-MePhe(4)-Gly(5)-enkephalin
Corpus Striatum
Narcotic Antagonists
alanylglycine
Naloxone
phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide
Dopamine

Keywords

  • Neurotransmitter release
  • Opioid receptor antagonists
  • Opioid receptors
  • Presynaptic inhibition
  • Somatostatin analogues

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Pharmacology

Cite this

Cyclic somatostatin analogues as potent antagonists at μ-, but not δ- and κ-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain. / Mulder, Arie H.; Wardeh, George; Hogenboom, François; Kazmierski, Wieslaw; Hruby, Victor J; Schoffelmeer, Anton N M.

In: European Journal of Pharmacology, Vol. 205, No. 1, 19.11.1991, p. 1-6.

Research output: Contribution to journalArticle

Mulder, Arie H. ; Wardeh, George ; Hogenboom, François ; Kazmierski, Wieslaw ; Hruby, Victor J ; Schoffelmeer, Anton N M. / Cyclic somatostatin analogues as potent antagonists at μ-, but not δ- and κ-opioid receptors mediating presynaptic inhibition of neurotransmitter release in the brain. In: European Journal of Pharmacology. 1991 ; Vol. 205, No. 1. pp. 1-6.
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abstract = "The opioid receptor antagonist properties of four conformaiionally constrained cyclic octapeptidc analogues of somatostatin were investigated using in vitro functional paradigms of μ-, δ- and κ-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pcn-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of μ-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMc)Phc-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenalinc (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of κ-opioid receptors by the cyclohcxylbenzeneacctamidc U69593 (0.02 μM) inhibited (by 40-45{\%}) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of δ-opioid receptors by [D-Scr2O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 μM) caused an inhibition (by 38-46{\%}) of striatal [14C]acctylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65{\%}) of 0.1 μM DAGO on cortical [3H]NA release. Thus, the cyclic octapcptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the μ-opioid receptors mediating presynaptic inhibition of NA release in the brain. The μ-rceeptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.",
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AU - Hruby, Victor J

AU - Schoffelmeer, Anton N M

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N2 - The opioid receptor antagonist properties of four conformaiionally constrained cyclic octapeptidc analogues of somatostatin were investigated using in vitro functional paradigms of μ-, δ- and κ-opioid receptors in the rat brain. The analogues examined were D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pcn-Thr-NH2 (CTAP), D-Tic-CTOP (TCTOP) and D-Tic-CTAP (TCTAP). Activation of μ-receptors by the enkephalin analogue Tyr-D-Ala-Gly-(NMc)Phc-Gly-ol (DAGO) inhibited the (electrically evoked) release of [3H]noradrenalinc (NA) from superfused cortical slices and this inhibitory effect was antagonized in a competitive fashion by all of the octapeptides tested (pA2 values: CTOP and CTAP 7.9-8.0, TCTOP and TCTAP 8.7-8.8). Selective activation of κ-opioid receptors by the cyclohcxylbenzeneacctamidc U69593 (0.02 μM) inhibited (by 40-45%) the release of [3H]dopamine (DA) from striatal slices, whereas selective activation of δ-opioid receptors by [D-Scr2O-t-butyl),Leu5]enkephalyl-Thr6 (DSTBULET; 0.1 μM) caused an inhibition (by 38-46%) of striatal [14C]acctylcholine (ACh) release. However, these inhibitory effects were not affected by any of the octapeptides in concentrations that caused full antagonism of the inhibitory effect (55-65%) of 0.1 μM DAGO on cortical [3H]NA release. Thus, the cyclic octapcptide somatostatin analogues CTOP, CTAP, TCTOP and TCTAP are potent and highly selective antagonists at the μ-opioid receptors mediating presynaptic inhibition of NA release in the brain. The μ-rceeptor affinity of the most potent of these antagonists, TCTOP and TCTAP, appears to be similar to that of naloxone but these antagonists have a much greater selectivity than the latter.

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