TY - JOUR AU - Borics, Attila AU - Mallareddy, Jayapelreddy AU - Timári, István AU - E Kövér, Katalin AU - Keresztes, Attila AU - Tóth, Géza TI - The Effect of Pro(2) Modifications on the Structural and Pharmacological Properties of Endomorphin-2. JF - JOURNAL OF MEDICINAL CHEMISTRY J2 - J MED CHEM VL - 55 PY - 2012 IS - 19 SP - 8418 EP - 8428 PG - 11 SN - 0022-2623 DO - 10.1021/jm300836n UR - https://m2.mtmt.hu/api/publication/2085025 ID - 2085025 AB - Endomorphins (EM-1 and EM-2) are selective, high affinity agonists of the mu-opioid (MOP) receptor, an important target in pain regulation. Their clinical use is impeded by their poor metabolic stability and limited entry to the central nervous system. In this study, the Pro(2) residue of EM-2 was modified systematically through substitution by hydroxyproline (Hyp), (S)-beta-homoproline (betaPro), 2-aminocyclopentene-1-carboxylic acid (DeltaAcpc), or 2-aminocyclohexene-1-carboxylic acid (DeltaAchc) to obtain stable MOP active compounds. Both Hyp(2) and betaPro(2) substitution decreased receptor affinity. Analogues incorporating alicyclic beta-amino acids exhibited diverse receptor binding properties, depending on the configuration of the substituent side-chain. (1S,2R)DeltaAcpc(2)-EM-2 was shown to have MOP affinity and selectivity comparable to those of EM-2 and proved to act as agonist while being resistant to proteolysis. NMR and molecular dynamics (MD) studies revealed that bent backbone structures are predominant in the most potent analogues, while their presence is less pronounced in ligands of lower receptor affinity. LA - English DB - MTMT ER - TY - JOUR AU - Fichna, J AU - Perlikowska, R AU - Wyrebska, A AU - Gach, K AU - Piekielna, J AU - do-Rego, JC AU - Tóth, Géza AU - Kluczyk, A AU - Janecki, T AU - Janecka, A TI - Effect of 2 ',6 '-dimethyl-L-tyrosine (Dmt) on pharmacological activity of cyclic endomorphin-2 and morphiceptin analogs JF - BIOORGANIC & MEDICINAL CHEMISTRY J2 - BIOORGAN MED CHEM VL - 19 PY - 2011 IS - 23 SP - 6977 EP - 6981 PG - 5 SN - 0968-0896 DO - 10.1016/j.bmc.2011.10.040 UR - https://m2.mtmt.hu/api/publication/1921927 ID - 1921927 AB - This study reports the synthesis and biological evaluation of a series of new side-chain-to-side-chain cyclized endomorphin-2 (EM-2) and morphiceptin analogs of a general structure Tyr-c(Xaa-Phe-Phe-Yaa) NH(2) or Tyr-c(Xaa-Phe-D-Pro-Yaa)NH(2), respectively, where Xaa and Yaa were L/D Asp or L/D Lys. Further modification of these analogs was achieved by introduction of 2',6'-dimethyl-L-tyrosine (Dmt) instead of Tyr in position 1. Peptides were synthesized by solid phase method and cleaved from the resin by a microwave-assisted procedure. Dmt(1)-substituted analogs displayed high affinity at the mu-opioid receptors, remained intact after incubation with the rat brain homogenate and showed remarkable, long-lasting mu-opioid receptor-mediated antinociceptive activity after central, but not peripheral administration. Our results demonstrate that cyclization is a promising strategy in the development of new opioid analgesics, but further modifications are necessary to enhance the blood-brain barrier permeability. (C) 2011 Published by Elsevier Ltd. LA - English DB - MTMT ER - TY - JOUR AU - Perlikowska, R AU - do-Rego, JC AU - Cravezic, A AU - Fichna, J AU - Wyrebska, A AU - Tóth, Géza AU - Janecka, A TI - Synthesis and biological evaluation of cyclic endomorphin-2 analogs JF - PEPTIDES J2 - PEPTIDES VL - 31 PY - 2010 IS - 2 SP - 339 EP - 345 PG - 7 SN - 0196-9781 DO - 10.1016/j.peptides.2009.12.002 UR - https://m2.mtmt.hu/api/publication/1921001 ID - 1921001 N1 - Megjegyzés-20964423 FU: Polish Ministry of Science [125/N-POLONIUM/2008/0, NN 401 0064 35]; : Medical University of Lodz [503-1156-2]; Polpharma Foundation For : Development of Polish Pharmacy and Medicine, the Platform of : Behavioural Analysis (SCAC, France) ; Conseil Regional de Haute : Normandie (France) FX: This work was supported by grants from the Polish Ministry of Science : No. 125/N-POLONIUM/2008/0 and No. NN 401 0064 35, from the Medical : University of Lodz No. 503-1156-2, Polpharma Foundation For Development : of Polish Pharmacy and Medicine, the Platform of Behavioural Analysis : (SCAC, France) and the grant from the Conseil Regional de Haute : Normandie (France). The authors wish to thank Jozef Cieslak for his : excellent technical assistance. Megjegyzés-22225307 DI: 10.1016/j.peptides.2009.12.002 AB - In our previous paper we reported synthesis and biological activity of two cyclic analogs of endomorphin-2 (EM-2): Tyr-c(Lys-Phe-Phe-Asp)-NH2 and Tyr-c(Asp-Phe-Phe-Lys)-NH2, achieved by making an amid bond between Lys and Asp side-chains. The first analog did not bind to the mu-opioid receptor, the affinity of the second one was very low. In the present study, we describe the synthesis of four novel cyclic analogs of similar structure, but with D-amino acids in position 2 (D-Lys or D-Asp). All new analogs displayed high affinity for the mu-opioid receptor, were much more stable than EM-2 in rat brain homogenate and showed remarkable antinociceptive activity after intracerebroventricular (i.c.v.) administration. Analgesic effect of the most potent cyclic analog, Tyr-C(D-Lys-Phe-Phe-Asp)NH2 Was much stronger and longer lasting than that of EM-2. This analog elicited analgesia also after peripheral administration and this effect was reversed by concomitant i.c.v. injection of the mu-opioid antagonist, beta-funaltrexamine, which indicated that antinociception was mediated by the mu-opioid receptor in the brain. Central action of the cyclic analog gives evidence that it was able to cross the blood-brain barrier, most likely due to the increased lipophilicity. Our results demonstrate that cyclization might be a promising strategy to enhance bioavailability of peptides and may serve a role in the development of novel endomorphin analogs with increased therapeutic potential. (C) 2009 Elsevier Inc. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Perlikowska, R AU - Gach, K AU - Fichna, J AU - Tóth, Géza AU - Walkowiak, B AU - do-Rego, JC AU - Janecka, A TI - Biological activity of endomorphin and [dmt(1)] endomorphin analogs with six-membered proline surrogates in position 2 JF - BIOORGANIC & MEDICINAL CHEMISTRY J2 - BIOORGAN MED CHEM VL - 17 PY - 2009 IS - 11 SP - 3789 EP - 3794 PG - 6 SN - 0968-0896 DO - 10.1016/j.bmc.2009.04.046 UR - https://m2.mtmt.hu/api/publication/1920710 ID - 1920710 N1 - Megjegyzés-22209519 DI: 10.1016/j.bmc.2009.04.046 Megjegyzés-22217299 DI: 10.1016/j.bmc.2009.04.046 LA - English DB - MTMT ER - TY - JOUR AU - Staniszewska, R AU - Fichna, J AU - Gach, K AU - Tóth, Géza AU - Poels, J AU - Broeck, JV AU - Janecka, A TI - Synthesis and biological activity of endomorphin-2 analogs incorporating piperidine-2-, 3- or 4-carboxylic acids instead of proline in position 2 JF - CHEMICAL BIOLOGY & DRUG DESIGN J2 - CHEM BIOL DRUG DES VL - 72 PY - 2008 IS - 1 SP - 91 EP - 94 PG - 4 SN - 1747-0277 DO - 10.1111/j.1747-0285.2008.00678.x UR - https://m2.mtmt.hu/api/publication/1917904 ID - 1917904 AB - Novel endomorphin-2 (EM-2) analogs have been synthesized, incorporating unnatural amino acids with six-membered heterocyclic rings, such as piperidine-2-, 3- and 4-carboxylic acids (Pip, Nip and Inp, respectively) instead of Pro in position 2. [(R)-Nip(2)]EM-2 displayed an extremely high affinity for the mu-opioid receptor with IC50 = 0.04 +/- 0.01 nM in comparison with IC50 = 0.69 +/- 0.03 nM for EM-2. This analog was also very potent in the aequorin luminescence-based functional calcium assay and showed significantly enhanced stability in rat brain homogenate. LA - English DB - MTMT ER - TY - JOUR AU - Leitgeb, Balázs AU - Tóth, Géza TI - Aromatic-aromatic and proline-aromatic interactions in endomorphin-1 and endomorphin-2 JF - EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY J2 - EUR J MED CHEM VL - 40 PY - 2005 SP - 674 EP - 686 PG - 13 SN - 0223-5234 DO - 10.1016/j.ejmech.2004.10.015 UR - https://m2.mtmt.hu/api/publication/1913931 ID - 1913931 LA - English DB - MTMT ER - TY - JOUR AU - Al-Khrasani, Mahmoud AU - Elor, G AU - Abbas, MY AU - Rónai, András TI - The effect of endomorphins on the release of H-3-norepinephrine from rat nucleus tractus solitarii slices JF - REGULATORY PEPTIDES J2 - REGUL PEPTIDES VL - 111 PY - 2003 IS - 1-3 SP - 97 EP - 101 PG - 5 SN - 0167-0115 DO - 10.1016/S0167-0115(02)00257-4 UR - https://m2.mtmt.hu/api/publication/1626917 ID - 1626917 AB - We used two, 3-min field stimulation cycles 30 min apart (S1, S2) in H-3-norepinephrine-loaded, superfused rat nucleus tractus solitarii-dorsal motor vagal nucleus (NTS-DVN) slices. The stimulation-induced release was expressed as the area above the baseline. Drugs were introduced 12 min before S2 and drug actions were characterized in terms of alterations of S2/S1 ratios. The S2/S1 ratio was 1.047 (0.946-1.159, n=4, geometric mean and 95% confidence interval) in controls and 0.336 (0.230-0.490, n=3), 0.726 (0.590-0.892, n=4), 0.613 (0.594-0.683, n=4) and 0.665 (0.500-0.886, n=4) in the presence of 10(-6) M clonidine, D-Ala(2),MePhe(4),Gly(5)-ol-enkephalin (DAMGO), endomorphin-1 (Tyr-Pro-Trp-Phe-NH2, EM-1) and -2 (Tyr-Pro-Phe-Phe-NH2, EM-2) [the latter two in the presence of 10(-4). M diprotin A, an inhibitor of dipeptidyl-aminopeptidase IV (DAP-IV) enzyme]. The effect of DAMGO at 10(-5) M was significantly higher than at 10(-6) M, whereas the effect of endomorphins did not differ at the two concentration levels. Diprotin A potentiated only very modestly the action of endomorphins. These data (a) confirm the presence of functional mu-opioid receptors in the vagal complex, (b) render it likely that the enzymic degradation of endomorphins is not a highly effective process in brain slices and (c) may suggest that the apparent ceiling in the effect of endomorphins might be related to their partial agonist property. (C) 2002 Elsevier Science B.V All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Bujdosó, Erika AU - Jászberényi, Miklós AU - Gardi, János AU - Földesi, Imre AU - Telegdy, Gyula TI - The involvement of dopamine and nitric oxide in the endocrine and behavioural action of endomorphine-1 JF - NEUROSCIENCE J2 - NEUROSCIENCE VL - 120 PY - 2003 IS - 1 SP - 261 EP - 268 PG - 8 SN - 0306-4522 DO - 10.1016/S0306-4522(03)00241-0 UR - https://m2.mtmt.hu/api/publication/247568 ID - 247568 AB - Previous publications have demonstrated a prominent central and corticotropin releasing hormone-mediated action of the endomorphins (EMs) on both open-field behaviour and the hypothalamo-pituitary-adrenal (HPA) axis. In the present experiments, the direct action of endomorphin-1 (EM1) on pituitary adrenocorticotropic hormone (ACTH) release, adrenal corticosterone secretion and the roles of nitric oxide (NO) and dopamine (DA) in the HPA and behavioural responses elicited by EM1 were investigated in mice. In vitro perifusion studies indicated that the action of EM1 on the HPA system appears to be confined to the hypothalamus, as EM1 did not influence the corticosterone secretion from adrenal slices and moderately attenuated the ACTH release from anterior pituitary slices. In in vivo experiments, N-G-nitro-(L)-arginine (L-NNArg) pretreatment brought about a profound inhibition of both the endocrine and the behavioural responses. On the other hand, haloperidol completely abolished the increases in square crossing and rearing, without affecting corticosterone release. The direct action of EMI on striatal DA release was therefore also investigated in an in vitro superfusion system. Although EM1 did not influence the basal release of tritiated DA, it significantly enhanced the transmitter release evoked by electric impulses and pretreatment with L-NNArg resulted in a considerable inhibition of the release elicited by EM1. In conclusion, our endocrine studies suggest an important role of NO in the mediation of the EM1-evoked corticosterone secretion. They also indicate that EM1 activates the HPA axis at a hypothalamic level and dopamine is not involved in this process. In contrast, the behavioural experiments reflect that the locomotor activation induced by EM1 is mediated by NO and dopamine, and the superfusion studies demonstrate that NO transmits the dopamine release enhancing effect of EM1. (C) 2003 IBRO. Published by Elsevier Science Ltd. All rights reserved. LA - English DB - MTMT ER - TY - JOUR AU - Tömböly, Csaba AU - Péter, Antal AU - Tóth, Géza TI - In vitro quantitative study of the degradation of endomorphins JF - PEPTIDES J2 - PEPTIDES VL - 23 PY - 2002 IS - 9 SP - 1573 EP - 1580 PG - 8 SN - 0196-9781 DO - 10.1016/S0196-9781(02)00100-6 UR - https://m2.mtmt.hu/api/publication/1322897 ID - 1322897 N1 - WoS:hiba:000178339300006 2019-03-02 02:14 cikkazonosító nem egyezik LA - English DB - MTMT ER -