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

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.