@article{MTMT:2085025, title = {The Effect of Pro(2) Modifications on the Structural and Pharmacological Properties of Endomorphin-2.}, url = {https://m2.mtmt.hu/api/publication/2085025}, author = {Borics, Attila and Mallareddy, Jayapelreddy and Timári, István and E Kövér, Katalin and Keresztes, Attila and Tóth, Géza}, doi = {10.1021/jm300836n}, journal-iso = {J MED CHEM}, journal = {JOURNAL OF MEDICINAL CHEMISTRY}, volume = {55}, unique-id = {2085025}, issn = {0022-2623}, abstract = {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.}, year = {2012}, eissn = {1520-4804}, pages = {8418-8428} } @article{MTMT:1921927, title = {Effect of 2 ',6 '-dimethyl-L-tyrosine (Dmt) on pharmacological activity of cyclic endomorphin-2 and morphiceptin analogs}, url = {https://m2.mtmt.hu/api/publication/1921927}, author = {Fichna, J and Perlikowska, R and Wyrebska, A and Gach, K and Piekielna, J and do-Rego, JC and Tóth, Géza and Kluczyk, A and Janecki, T and Janecka, A}, doi = {10.1016/j.bmc.2011.10.040}, journal-iso = {BIOORGAN MED CHEM}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY}, volume = {19}, unique-id = {1921927}, issn = {0968-0896}, abstract = {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.}, year = {2011}, eissn = {1464-3391}, pages = {6977-6981} } @article{MTMT:1921001, title = {Synthesis and biological evaluation of cyclic endomorphin-2 analogs}, url = {https://m2.mtmt.hu/api/publication/1921001}, author = {Perlikowska, R and do-Rego, JC and Cravezic, A and Fichna, J and Wyrebska, A and Tóth, Géza and Janecka, A}, doi = {10.1016/j.peptides.2009.12.002}, journal-iso = {PEPTIDES}, journal = {PEPTIDES}, volume = {31}, unique-id = {1921001}, issn = {0196-9781}, abstract = {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.}, year = {2010}, eissn = {1873-5169}, pages = {339-345} } @article{MTMT:1920710, title = {Biological activity of endomorphin and [dmt(1)] endomorphin analogs with six-membered proline surrogates in position 2}, url = {https://m2.mtmt.hu/api/publication/1920710}, author = {Perlikowska, R and Gach, K and Fichna, J and Tóth, Géza and Walkowiak, B and do-Rego, JC and Janecka, A}, doi = {10.1016/j.bmc.2009.04.046}, journal-iso = {BIOORGAN MED CHEM}, journal = {BIOORGANIC & MEDICINAL CHEMISTRY}, volume = {17}, unique-id = {1920710}, issn = {0968-0896}, year = {2009}, eissn = {1464-3391}, pages = {3789-3794} } @article{MTMT:1917904, title = {Synthesis and biological activity of endomorphin-2 analogs incorporating piperidine-2-, 3- or 4-carboxylic acids instead of proline in position 2}, url = {https://m2.mtmt.hu/api/publication/1917904}, author = {Staniszewska, R and Fichna, J and Gach, K and Tóth, Géza and Poels, J and Broeck, JV and Janecka, A}, doi = {10.1111/j.1747-0285.2008.00678.x}, journal-iso = {CHEM BIOL DRUG DES}, journal = {CHEMICAL BIOLOGY & DRUG DESIGN}, volume = {72}, unique-id = {1917904}, issn = {1747-0277}, abstract = {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.}, year = {2008}, eissn = {1747-0285}, pages = {91-94} } @article{MTMT:1913931, title = {Aromatic-aromatic and proline-aromatic interactions in endomorphin-1 and endomorphin-2}, url = {https://m2.mtmt.hu/api/publication/1913931}, author = {Leitgeb, Balázs and Tóth, Géza}, doi = {10.1016/j.ejmech.2004.10.015}, journal-iso = {EUR J MED CHEM}, journal = {EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY}, volume = {40}, unique-id = {1913931}, issn = {0223-5234}, year = {2005}, eissn = {1768-3254}, pages = {674-686} } @article{MTMT:1626917, title = {The effect of endomorphins on the release of H-3-norepinephrine from rat nucleus tractus solitarii slices}, url = {https://m2.mtmt.hu/api/publication/1626917}, author = {Al-Khrasani, Mahmoud and Elor, G and Abbas, MY and Rónai, András}, doi = {10.1016/S0167-0115(02)00257-4}, journal-iso = {REGUL PEPTIDES}, journal = {REGULATORY PEPTIDES}, volume = {111}, unique-id = {1626917}, issn = {0167-0115}, abstract = {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.}, keywords = {PEPTIDES; RECEPTOR; CLONIDINE; CNS; ENDOMORPHIN-2; ENDOMORPHIN-1; diprotin A; D-Ala(2),MePhe(4),Gly(5)-ol-enkephalin (DAMGO)}, year = {2003}, eissn = {1873-1686}, pages = {97-101}, orcid-numbers = {Al-Khrasani, Mahmoud/0000-0001-8488-3266} } @article{MTMT:247568, title = {The involvement of dopamine and nitric oxide in the endocrine and behavioural action of endomorphine-1}, url = {https://m2.mtmt.hu/api/publication/247568}, author = {Bujdosó, Erika and Jászberényi, Miklós and Gardi, János and Földesi, Imre and Telegdy, Gyula}, doi = {10.1016/S0306-4522(03)00241-0}, journal-iso = {NEUROSCIENCE}, journal = {NEUROSCIENCE}, volume = {120}, unique-id = {247568}, issn = {0306-4522}, abstract = {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.}, year = {2003}, eissn = {1873-7544}, pages = {261-268}, orcid-numbers = {Jászberényi, Miklós/0000-0002-7287-7771; Földesi, Imre/0000-0002-3329-8136; Telegdy, Gyula/0000-0003-1734-4128} } @article{MTMT:1322897, title = {In vitro quantitative study of the degradation of endomorphins}, url = {https://m2.mtmt.hu/api/publication/1322897}, author = {Tömböly, Csaba and Péter, Antal and Tóth, Géza}, doi = {10.1016/S0196-9781(02)00100-6}, journal-iso = {PEPTIDES}, journal = {PEPTIDES}, volume = {23}, unique-id = {1322897}, issn = {0196-9781}, year = {2002}, eissn = {1873-5169}, pages = {1573-1580} }