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1.
Sci Rep ; 9(1): 5771, 2019 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-30962495

RESUMO

Here, we report the chemical synthesis of two DPDPE analogues 7a (NOVA1) and 7b (NOVA2). This entailed the solid-phase synthesis of two enkephalin precursor chains followed by a CuI-catalyzed azide-alkyne cycloaddition, with the aim of improving in vivo analgesic efficacy versus DPDPE. NOVA2 showed good affinity and selectivity for the µ-opioid receptor (KI of 59.2 nM, EC50 of 12.9 nM, EMax of 87.3%), and long lasting anti-nociceptive effects in mice when compared to DPDPE.


Assuntos
Analgésicos/síntese química , Química Click/métodos , D-Penicilina (2,5)-Encefalina/análogos & derivados , Analgésicos/farmacologia , Animais , Células CHO , Cricetinae , Cricetulus , Reação de Cicloadição/métodos , D-Penicilina (2,5)-Encefalina/síntese química , D-Penicilina (2,5)-Encefalina/farmacologia , Humanos , Masculino , Camundongos , Ligação Proteica , Receptores Opioides mu/metabolismo
2.
Biochem Biophys Res Commun ; 318(2): 335-40, 2004 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-15120606

RESUMO

Pyrene possesses unique spectroscopic properties such as a high quantum yield, a long half-life in the excited state, and the ability to form excimers when in proximity to each other in the excited state. These properties allow pyrenylalanine, which is a pyrene moiety incorporated into an amino acid, to be used as a fluorescent probe in peptides and proteins. The common route for the synthesis of pyrenylalanine involves 5 steps, with subsequent separation of the two isomers by recrystallization. This paper reports a novel 3-step asymmetric synthesis of pyrenylalanine with high enantioselectivity, good yields, and facile isomer purification. After synthesis, pyrenylalanine was incorporated into a series of opioid, CCK, and melanotropin peptide ligands in order to study the effects of aromaticity, lipophilicity, and steric properties on their potency and efficacy at their corresponding biological receptors. The change in binding and efficacy of the labeled ligands as compared to the unlabeled ligands demonstrates the possible role of lipophilicity/aromaticity in the binding and signal transduction of the ligand-receptor interaction.


Assuntos
Alanina/análogos & derivados , Colecistocinina/análogos & derivados , Hormônios Estimuladores de Melanócitos/química , Entorpecentes/química , Pirenos/síntese química , Alanina/síntese química , Alanina/metabolismo , Sequência de Aminoácidos , Colecistocinina/metabolismo , AMP Cíclico/metabolismo , D-Penicilina (2,5)-Encefalina/análogos & derivados , D-Penicilina (2,5)-Encefalina/metabolismo , Guanosina Trifosfato/metabolismo , Humanos , Ligantes , Hormônios Estimuladores de Melanócitos/metabolismo , Estrutura Molecular , Entorpecentes/metabolismo , Oligopeptídeos/química , Oligopeptídeos/metabolismo , Ligação Proteica , Pirenos/química , Pirenos/metabolismo , Receptores de Melanocortina/genética , Receptores de Melanocortina/metabolismo , Receptores Opioides delta/metabolismo , Estereoisomerismo
3.
J Pharmacol Exp Ther ; 304(2): 827-32, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12538839

RESUMO

A lanthionine enkephalin derivative, Tyr-c[D-Val(L)-Gly-Phe-D-Ala(L)]-OH (DV(L)(2)DA(L)(5)LanEnk), where Val(L) and Ala(L) denote the lanthionine amino acid ends linked via a monosulfide bridge to form the lanthionine structure, was synthesized. It was found to possess selectivity for and potency at the delta versus mu opioid receptor as defined by binding studies and by its respective activity on the mouse vas deferens compared with the guinea pig ileum. The agent produced a potent analgesia after intrathecal and intraperitoneal delivery with ED(50) values being, respectively, 0.19 mucrog and 0.49 mg/kg. The effects of the agent were reversed by the delta-selective antagonist naltrindole. These analgesic actions occurred at doses that had no effect upon general behavior or motor function. These results suggest a potent delta-preferring agent suitable for development as a systemic delta opioid analgesic.


Assuntos
Alanina/análogos & derivados , Alanina/farmacologia , Analgésicos Opioides/farmacologia , Encefalinas/farmacologia , Receptores Opioides delta/fisiologia , Medula Espinal/efeitos dos fármacos , Alanina/química , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , D-Penicilina (2,5)-Encefalina/análogos & derivados , D-Penicilina (2,5)-Encefalina/farmacologia , Encefalinas/química , Cobaias , Técnicas In Vitro , Masculino , Camundongos , Medição da Dor/efeitos dos fármacos , Medição da Dor/métodos , Ratos , Ratos Sprague-Dawley , Receptores Opioides delta/agonistas , Medula Espinal/fisiologia , Sulfetos
4.
J Pharmacol Exp Ther ; 295(3): 960-6, 2000 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11082429

RESUMO

The Phe(1) cyclic tetrapeptide Phe-c[D-Cys-Phe-D-Pen]NH(2) (Et) (JH-54) has been shown previously to exhibit high affinity and selectivity for the mu-opioid receptor. To examine the role of the Phe(1) residue in the unexpected high affinity of this peptide, 11 analogs of JH-54 have been synthesized and evaluated for opioid ligand binding and for efficacy using the [(35)S]GTPgammaS assay. Alteration of the bridging groups between the D-Cys(2) and D-Pen(4) residues of JH-54 from dithioether to disulfide revealed the importance of the relative position of the aromatic rings of the first and third residues in determining mu- and delta-affinities. The one carbon distance between the alpha carbon and phenyl ring in the N-terminal residue was critical. Additional steric bulk in the N-terminal Phe(1) residue was accommodated without large reductions in affinity in two naphthyl analogs, but not with 3, 3-(diphenyl)alanine. Conformational restriction of the Calpha-Cbeta and/or Cbeta-Cgamma bonds had little effect on affinities in two peptides with 2-amino-2-carboxytetralin in position 1, but it abolished activity in an isoquinoline analog and differentially altered activity in four phenylproline(1)-containing peptides. Most surprisingly, replacement of the Phe(1) aromatic ring with cyclohexyl resulted in a peptide of moderate affinity (K(i) = 32.5 nM) and potency (EC(50) = 58.8 nM). Thus, the tyrosyl para-hydroxyl substituent and even aromaticity in the N-terminal amino acid of these tetrapeptides are shown to be important, but not critical, features for mu-opioid receptor affinity, agonist potency, and efficacy.


Assuntos
D-Penicilina (2,5)-Encefalina/análogos & derivados , Peptídeos Cíclicos/farmacologia , Receptores Opioides mu/agonistas , Animais , Células Cultivadas , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Cobaias , Ensaio Radioligante , Relação Estrutura-Atividade , Tirosina
5.
J Neurochem ; 75(1): 424-35, 2000 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-10854288

RESUMO

[D-Pen(2),D-Pen(5)]-Enkephalin (DPDPE) is an enzymatically stable delta-opioid receptor-selective peptide, which was modified by the trimethylation of the Phe(4) residue to give beta-methyl-2', 6'-dimethylphenylalanine (TMP), resulting in four conformations : (2R,3S)-beta-Phe-DPDPE, (2R,3R)-beta-Phe-DPDPE, (2R, 3S)-beta-Phe-DPDPE, and (2S,3R)-beta-Phe-DPDPE. Synthesis was by solid-phase techniques using enantiomerically pure amino acids to give the four optically pure diastereoisomer peptides. The potency and selectivity (delta- versus mu-opioid receptor) were evaluated by radioreceptor binding in rat brain, with a mu/delta ratio decrease for all TMP conformations, compared with the parent compound (DPDPE). Octanol/buffer distribution analysis showed enhanced lipophilicity of all TMP forms, with a sixfold enhancement associated with (2S,3S)-TMP. In situ vascular perfusion in anesthetized rats showed a 1.6-fold (p < 0.01) increase in the ratio of brain uptake for (2S,3S)-TMP and a 1.5-fold (p < 0.01) decrease in uptake for (2R,3R)-TMP. Saturability of (2S,3S)-TMP was shown (p < 0.01) against 100 microM unlabeled DPDPE, showing a shared nondiffusionary transport system. P-glycoprotein affinity was shown in situ for the parent and (2S,3S)-TMP (p < 0.01). Protein binding capacity of the TMP compounds in rat plasma and in situ mammalian bovine serum albumin-Ringer showed (2R,3S)-TMP and (2S,3R)-TMP with the lowest degree of protein binding (p < 0.01), and (2S,3S)-TMP and (2R,3R)-TMP with comparable affinities to DPDPE. Analgesia, via intravenous administration, showed significantly reduced (p < 0.01) end effect and time course for (2R,3R)-TMP, (2R,3S)-TMP, and (2S, 3R)-TMP as compared with DPDPE. These results demonstrate that topographical modification in a conformationally restricted peptide can significantly modulate potency and receptor selectivity, binding capacity, enzymatic stability, lipophilicity, P-glycoprotein affinity, and blood-brain barrier permeability, resulting in a change of bioavailability, and thereby provides insight for future peptide drug design.


Assuntos
Alanina/análogos & derivados , D-Penicilina (2,5)-Encefalina/análogos & derivados , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Alanina/química , Alanina/metabolismo , Analgesia , Animais , Barreira Hematoencefálica , Encéfalo/irrigação sanguínea , Encéfalo/metabolismo , Capilares/metabolismo , Bovinos , Endotélio Vascular/metabolismo , D-Penicilina (2,5)-Encefalina/química , Feminino , Metilação , Conformação Molecular , Ratos , Ratos Sprague-Dawley , Estereoisomerismo , Relação Estrutura-Atividade
6.
Biopolymers ; 53(7): 565-80, 2000 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10766952

RESUMO

A comparative molecular modeling study of delta-opioid ligands was performed under the assumption that potent peptide and nonpeptide agonists may have common three-dimensional (3D) arrangement of pharmacophore groups upon binding to the delta-receptor. Low-energy conformations of the agonists 7-spiroindanyloxymorphone (SIOM) and 2-methyl-4a-alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a-alpha-octahydro-quinolino[2,3,3-g]isoquinoline (TAN-67), and a partial agonist oxomorphindole (OMI) were determined by high-temperature molecular dynamics (MD). A good spatial overlap was found for the pharmacophore groups of SIOM, TAN-67, and OMI, including the basic nitrogen, phenol hydroxyl, and two aromatic ring. Based on this overlap we proposed a 3D pharmacophore model for nonpeptide delta-opioid agonists with a distance of 7.0 +/- 1.3 A between the two aromatic rings and of 8.2 +/- 1.0 A between the nitrogen and phenyl ring. The potent and highly delta-opioid receptor selective agonist [(2S,3R)-TMT(1)]DPDPE, which shares global backbone constraints of the 14-membered disulfide cycle and a strong preference for the trans rotamer of the TMT(1) side chain, was chosen as a peptide template of the delta-opioid pharmacophore. Extensive MD simulations at 300 K with the AMBER force field were performed for [(2S,3R)-TMT(1)]DPDPE and the less potent [(2S, 3S)-TMT(1)]DPDPE analogue. Multiple MD trajectories were collected for each peptide starting from the x-ray structures of DPDPE and [L-Ala(3)]DPDPE and from models proposed in the literature. Low-energy MD conformations were filtered by the nonpeptide pharmacophore query and then directly superimposed with SIOM, OMI, and TAN-67. Two conformers of [(2S,3R)-TMT(1)]DPDPE that showed the best overlap with the nonpeptide pharmacophore (rms deviation

Assuntos
D-Penicilina (2,5)-Encefalina/química , Ligantes , Oximorfona/análogos & derivados , Peptídeos/química , Quinolinas/química , Receptores Opioides delta/química , Compostos de Espiro/química , Analgésicos/química , Sítios de Ligação , D-Penicilina (2,5)-Encefalina/análogos & derivados , Modelos Moleculares , Conformação Molecular , Morfolinas/química , Oximorfona/química , Relação Estrutura-Atividade
7.
Peptides ; 20(10): 1229-38, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10573295

RESUMO

The utility of a drug depends on its ability to reach appropriate receptors at the target tissue and remain metabolically stable to produce the desired effect. To improve central nervous system entry of the opioid analgesic [D-Pen2, L-Pen5, Phe6] Enkephalin (DPLPE-Phe), our research group synthesized analogs that had chloro, bromo, fluoro, and iodo halogens on the para positions of the phenylalanine-4 residue. This study reports on investigation of the effect of halogenation on stability, lipophilicity, and in vitro blood-brain barrier permeability of a novel enkephalin analog DPLPE-Phe. The stability of each halogenated DPLPE-Phe analog as well as the amidated and nonamidated parent peptide was tested in plasma and brain. All peptides tested had a half-time disappearance >300 min except for DPLPE-Phe-NH2, which was found to have a half-life of 30 min in plasma. Octanol/saline distribution studies indicated addition of halogens to DPLPE-Phe-OH significantly increased lipophilicity except for p-[F-Phe4]DPLPE-Phe-OH. p-[Cl-Phe4]DPLPE-Phe-OH exhibited the most pronounced increase in lipophilicity. Para-bromo and para-chloro halogen additions significantly enhanced in vitro blood-brain barrier permeability, providing evidence for improved delivery to the central nervous system.


Assuntos
Barreira Hematoencefálica/fisiologia , D-Penicilina (2,5)-Encefalina/análogos & derivados , Encefalinas/farmacocinética , Halogênios/metabolismo , Peptídeos/farmacocinética , Animais , Bovinos , D-Penicilina (2,5)-Encefalina/química , D-Penicilina (2,5)-Encefalina/farmacocinética , Camundongos , Octanóis/metabolismo , Permeabilidade , Cloreto de Sódio/metabolismo
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