TY - JOUR
T1 - Structure-activity relationships of naturally occurring and synthetic opioid tetrapeptides acting on locus coeruleus neurons
AU - Yang, Y. R.
AU - Chiu, T. H.
AU - Chen, C. L.
N1 - Funding Information:
This work was supported in part by grant no. NSC 84-2331-B-010-111 from the National Science Council (to T.H.C.). We appreciate Mr. Al Vendouris for his editing and are grateful to his English language consultancy.
PY - 1999
Y1 - 1999
N2 - Intracellular recording was used to study the effects of eight opioid tetrapeptides with similar amino acid sequences, namely endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), morphiceptin (Tyr-Pro-Phe-Pro-NH2), hemorphin-4 (Tyr-Pro-Trp-Thr), Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), TAPS (Tyr-d-Arg-Phe-Sar) and DALDA (Tyr-d-Arg-Phe-Lys-NH2), on neurons of the rat locus coeruleus, using a submerged brain slice preparation. All the tetrapeptides inhibited the spontaneous firing of all neurons of the locus coeruleus tested. Higher concentrations also caused hyperpolarization of the neurons and a reduction in input resistance. These inhibitory effects were rapidly and completely reversed by CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a selective μ-opioid receptor antagonist). The IC50 of the opioid tetrapeptides, in terms of inhibition of spontaneous firing of locus coeruleus neurons, as compared to the concentrations which produced a 5-mV hyperpolarization (HC(5 mV)) were calculated, giving the same rank order of potency: TAPS (IC50=1.9 nM, HC(5 mV)=3.4 nM)>endomorphin-1 (IC50=8.8 nM, HC(5 mV)=22.1 nM) and endomorphin-2 (IC50=5.3 nM, HC(5 mV)=16.1 nM)>DALDA (IC50=20 nM, HC(5 mV)=143 nM)>morphiceptin (IC50=65 nM, HC(5 mV)=335 nM)>Tyr-W-MIF-1 (IC50=3.8 μM, HC(5 mV)=6.7 μM)>hemorphin-4 (IC50=6.7 μM, HC(5 mV)=36.9 μM)>Tyr-MIF-1 (IC50=37.5 μM, HC(5 mV)=76.2 μM). Comparison of the ability of endomorphin-1 and endomorphin-2 to inhibit spontaneous firing based on single-cell recordings (n=5) showed these two peptides to be equipotent. Based on these results, the structure-activity relationships of these opioid tetrapeptides are discussed herein. Copyright (C) 1999 Elsevier Science B.V.
AB - Intracellular recording was used to study the effects of eight opioid tetrapeptides with similar amino acid sequences, namely endomorphin-1 (Tyr-Pro-Trp-Phe-NH2), endomorphin-2 (Tyr-Pro-Phe-Phe-NH2), morphiceptin (Tyr-Pro-Phe-Pro-NH2), hemorphin-4 (Tyr-Pro-Trp-Thr), Tyr-MIF-1 (Tyr-Pro-Leu-Gly-NH2), Tyr-W-MIF-1 (Tyr-Pro-Trp-Gly-NH2), TAPS (Tyr-d-Arg-Phe-Sar) and DALDA (Tyr-d-Arg-Phe-Lys-NH2), on neurons of the rat locus coeruleus, using a submerged brain slice preparation. All the tetrapeptides inhibited the spontaneous firing of all neurons of the locus coeruleus tested. Higher concentrations also caused hyperpolarization of the neurons and a reduction in input resistance. These inhibitory effects were rapidly and completely reversed by CTAP (d-Phe-Cys-Tyr-d-Trp-Arg-Thr-Pen-Thr-NH2, a selective μ-opioid receptor antagonist). The IC50 of the opioid tetrapeptides, in terms of inhibition of spontaneous firing of locus coeruleus neurons, as compared to the concentrations which produced a 5-mV hyperpolarization (HC(5 mV)) were calculated, giving the same rank order of potency: TAPS (IC50=1.9 nM, HC(5 mV)=3.4 nM)>endomorphin-1 (IC50=8.8 nM, HC(5 mV)=22.1 nM) and endomorphin-2 (IC50=5.3 nM, HC(5 mV)=16.1 nM)>DALDA (IC50=20 nM, HC(5 mV)=143 nM)>morphiceptin (IC50=65 nM, HC(5 mV)=335 nM)>Tyr-W-MIF-1 (IC50=3.8 μM, HC(5 mV)=6.7 μM)>hemorphin-4 (IC50=6.7 μM, HC(5 mV)=36.9 μM)>Tyr-MIF-1 (IC50=37.5 μM, HC(5 mV)=76.2 μM). Comparison of the ability of endomorphin-1 and endomorphin-2 to inhibit spontaneous firing based on single-cell recordings (n=5) showed these two peptides to be equipotent. Based on these results, the structure-activity relationships of these opioid tetrapeptides are discussed herein. Copyright (C) 1999 Elsevier Science B.V.
KW - Locus coeruleus
KW - Opioid tetrapeptide
KW - Structure-activity relationship
KW - μ-Opioid receptor agonist
UR - http://www.scopus.com/inward/record.url?scp=0033036795&partnerID=8YFLogxK
U2 - 10.1016/S0014-2999(99)00210-1
DO - 10.1016/S0014-2999(99)00210-1
M3 - Article
C2 - 10395016
AN - SCOPUS:0033036795
SN - 0014-2999
VL - 372
SP - 229
EP - 236
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -