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1.
Cell Mol Neurobiol ; 41(5): 977-993, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32424771

RESUMO

Mu opioid receptors (MOR-1) mediate the biological actions of clinically used opioids such as morphine, oxycodone, and fentanyl. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating multiple splice variants. One type of splice variants are truncated variants containing only six transmembrane domains (6TM) that mediate the analgesic action of novel opioid drugs such as 3'-iodobenzoylnaltrexamide (IBNtxA). Previously, we have shown that IBNtxA is a potent analgesic effective in a spectrum of pain models but lacks many side-effects associated with traditional opiates. In order to investigate the targets labeled by IBNtxA, we synthesized two arylazido analogs of IBNtxA that allow photolabeling of mouse mu opioid receptors (mMOR-1) in transfected cell lines and mMOR-1 protein complexes that may comprise the 6TM sites in mouse brain. We demonstrate that both allyl and alkyne arylazido derivatives of IBNtxA efficiently radio-photolabeled mMOR-1 in cell lines and MOR-1 protein complexes expressed either exogenously or endogenously, as well as found in mouse brain. In future, design and application of such radio-photolabeling ligands with a conjugated handle will provide useful tools for further isolating or purifying MOR-1 to investigate site specific ligand-protein contacts and its signaling complexes.


Assuntos
Analgésicos Opioides/metabolismo , Azidas/metabolismo , Encéfalo/metabolismo , Naltrexona/análogos & derivados , Marcadores de Fotoafinidade/metabolismo , Receptores Opioides/metabolismo , Analgésicos Opioides/síntese química , Animais , Azidas/síntese química , Encéfalo/efeitos dos fármacos , Células CHO , Linhagem Celular , Cricetinae , Cricetulus , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Naltrexona/síntese química , Naltrexona/metabolismo , Marcadores de Fotoafinidade/síntese química , Ligação Proteica/fisiologia , Ensaio Radioligante/métodos
2.
Elife ; 102021 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-33555255

RESUMO

Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here, we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial in vivo profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.


Assuntos
Morfinanos/química , Receptores Opioides kappa/química , Receptores Opioides mu/química , Motivos de Aminoácidos , Analgésicos/química , Analgésicos/metabolismo , Animais , Sítios de Ligação , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/metabolismo , Relação Estrutura-Atividade
3.
Bioorg Med Chem Lett ; 20(6): 1965-8, 2010 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-20153643

RESUMO

Analog 8, a 3-pyridinecarbonitrile with an (E)-2-[6-[(4-methylpiperazin-1-yl)methyl]pyridin-2-yl]vinyl group at C-5, had an IC(50) value of 1.1 nM for the inhibition of PKCtheta and potently blocked the production of IL-2 in both stimulated murine T cells (IC(50)=34 nM) and human whole blood (IC(50)=500 nM).


Assuntos
Isoenzimas/antagonistas & inibidores , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Animais , Humanos , Interleucina-2/biossíntese , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Microssomos Hepáticos/enzimologia , Nitrilas/química , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/química , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
4.
Bioorg Med Chem Lett ; 20(2): 632-5, 2010 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-19959359

RESUMO

8,8-Diphenyl-2,3,4,8-tetrahydroimidazo[1,5-a]pyrimidin-6-amine (1) was identified through HTS, as a weak (micromolar) inhibitor of BACE1. X-Ray crystallographic studies indicate the 2-aminoimidazole ring forms key H-bonding interactions with Asp32 and Asp228 in the catalytic site of BACE1. Lead optimization using structure-based focused libraries led to the identification of low nanomolar BACE1 inhibitors such as 20b with substituents which extend from the S(1) to the S(3) pocket.


Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Inibidores Enzimáticos/química , Hidantoínas/química , Imidazóis/química , Secretases da Proteína Precursora do Amiloide/metabolismo , Sítios de Ligação , Domínio Catalítico , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Humanos , Hidantoínas/síntese química , Hidantoínas/farmacologia , Ligação de Hidrogênio , Imidazóis/síntese química , Imidazóis/farmacologia
5.
Bioorg Med Chem Lett ; 19(18): 5423-5, 2009 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-19682896

RESUMO

We earlier reported that 3-pyridinecarbonitriiles with a 4-methylindolyl-5-amino group at C-4 and a phenyl group at C-5 were inhibitors of PKCtheta. Keeping the group at C-4 of the pyridine core constant, we varied the water solubilizing group on the phenyl ring at C-5 and then replaced the C-5 phenyl ring with several monocyclic heteroaryl rings, including furan, thiophene and pyridine. Analog 6e with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-2-furyl group C-5 had an IC50 value of 4.5 nM for the inhibition of PKCtheta.


Assuntos
Isoenzimas/antagonistas & inibidores , Isoenzimas/metabolismo , Nitrilas/química , Nitrilas/farmacologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/química , Piridinas/farmacologia , Animais , Concentração Inibidora 50 , Isoenzimas/genética , Camundongos , Camundongos Knockout , Proteína Quinase C/genética , Proteína Quinase C-theta , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
6.
Bioorg Med Chem Lett ; 19(13): 3623-6, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19447612

RESUMO

The key intermediate, 4-chloro-5-iodo-3-pyridinecarbonitrile, allowed for ready optimization of the PKCtheta inhibitory activity of a series of 3-pyridinecarbonitriles. Analog 13b with a 4-methylindol-5-ylamino group at C-4 and a 4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl group at C-5 had an IC(50) value of 7.4nM for the inhibition of PKCtheta.


Assuntos
Indóis/química , Isoenzimas/antagonistas & inibidores , Nitrilas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Animais , Indóis/síntese química , Indóis/farmacologia , Isoenzimas/metabolismo , Camundongos , Nitrilas/síntese química , Nitrilas/farmacologia , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Relação Estrutura-Atividade
8.
Bioorg Med Chem Lett ; 19(19): 5799-802, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19703774

RESUMO

We previously reported that a 3-pyridinecarbonitrile analog with a furan substituent at C-5 and a 4-methylindol-5-ylamino substituent at C-4, 1, was a potent inhibitor of PKCtheta (IC50=4.5 nM). Replacement of the C-5 furan ring of 1 with bicyclic heteroaryl rings, led to compounds with significantly improved potency against PKCtheta. Analog 6b with a 4-methylindol-5-ylamino group at C-4 and a 5-[(4-methylpiperazin-1-yl)methyl]-1-benzofuran-2-yl group at C-5 had an IC50 value of 0.28 nM for the inhibition of PKCtheta.


Assuntos
Aminopiridinas/química , Isoenzimas/antagonistas & inibidores , Nitrilas/química , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/química , Piridinas/química , Aminopiridinas/síntese química , Aminopiridinas/farmacologia , Animais , Benzofuranos/síntese química , Benzofuranos/química , Benzofuranos/farmacologia , Meia-Vida , Humanos , Interleucina-2/metabolismo , Isoenzimas/metabolismo , Camundongos , Microssomos Hepáticos/metabolismo , Nitrilas/síntese química , Nitrilas/farmacologia , Proteína Quinase C/metabolismo , Proteína Quinase C-theta , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Ratos , Linfócitos T/imunologia , Linfócitos T/metabolismo
9.
J Med Chem ; 59(18): 8381-97, 2016 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-27556704

RESUMO

Natural products found in Mitragyna speciosa, commonly known as kratom, represent diverse scaffolds (indole, indolenine, and spiro pseudoindoxyl) with opioid activity, providing opportunities to better understand opioid pharmacology. Herein, we report the pharmacology and SAR studies both in vitro and in vivo of mitragynine pseudoindoxyl (3), an oxidative rearrangement product of the corynanthe alkaloid mitragynine. 3 and its corresponding corynantheidine analogs show promise as potent analgesics with a mechanism of action that includes mu opioid receptor agonism/delta opioid receptor antagonism. In vitro, 3 and its analogs were potent agonists in [(35)S]GTPγS assays at the mu opioid receptor but failed to recruit ß-arrestin-2, which is associated with opioid side effects. Additionally, 3 developed analgesic tolerance more slowly than morphine, showed limited physical dependence, respiratory depression, constipation, and displayed no reward or aversion in CPP/CPA assays, suggesting that analogs might represent a promising new generation of novel pain relievers.


Assuntos
Analgésicos Opioides/farmacologia , Receptores Opioides delta/antagonistas & inibidores , Receptores Opioides mu/agonistas , Alcaloides de Triptamina e Secologanina/farmacologia , beta-Arrestina 2/metabolismo , Analgésicos Opioides/química , Animais , Linhagem Celular , Humanos , Masculino , Camundongos , Mitragyna/química , Simulação de Acoplamento Molecular , Receptores Opioides delta/metabolismo , Receptores Opioides mu/metabolismo , Alcaloides de Triptamina e Secologanina/química
10.
ACS Chem Neurosci ; 6(11): 1813-24, 2015 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-26325040

RESUMO

3-Iodobenzoyl naltrexamine (IBNtxA) is a potent analgesic belonging to the pharmacologically diverse 6ß-amidoepoxymorphinan group of opioids. We present the synthesis and pharmacological evaluation of five analogs of IBNtxA. The scaffold of IBNtxA was modified by removing the 14-hydroxy group, incorporating a 7,8 double bond and various N-17 alkyl substituents. The structural modifications resulted in analogs with picomolar affinities for opioid receptors. The lead compound (MP1104) was found to exhibit approximately 15-fold greater antinociceptive potency (ED50 = 0.33 mg/kg) compared with morphine, mediated through the activation of kappa- and delta-opioid receptors. Despite its kappa agonism, this lead derivative did not cause place aversion or preference in mice in a place-conditioning assay, even at doses 3 times the analgesic ED50. However, pretreatment with the lead compound prevented the reward behavior associated with cocaine in a conditioned place preference assay. Together, these results suggest the promise of dual acting kappa- and delta-opioid receptor agonists as analgesics and treatments for cocaine addiction.


Assuntos
Analgésicos Opioides/síntese química , Analgésicos Opioides/farmacologia , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Morfinanos/síntese química , Morfinanos/farmacologia , Analgésicos Opioides/química , Animais , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Avaliação Pré-Clínica de Medicamentos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Morfinanos/química , Naltrexona/análogos & derivados , Naltrexona/química , Nociceptividade/efeitos dos fármacos , Nociceptividade/fisiologia , Membro 1 do Grupo F da Subfamília 1 de Receptores Nucleares/farmacologia , Distribuição Aleatória , Receptores Opioides delta/agonistas , Receptores Opioides delta/metabolismo , Receptores Opioides kappa/agonistas , Receptores Opioides kappa/genética , Receptores Opioides kappa/metabolismo , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Recompensa , Comportamento Espacial/efeitos dos fármacos , Comportamento Espacial/fisiologia
11.
ACS Chem Neurosci ; 6(9): 1570-7, 2015 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-26148793

RESUMO

We report a novel approach to synthesize carfentanil amide analogues utilizing the isocyanide-based four-component Ugi multicomponent reaction. A small library of bis-amide analogues of carfentanil was created using N-alkylpiperidones, aniline, propionic acid, and various aliphatic isocyanides. Our lead compound showed high affinity for mu (MOR) and delta opioid receptors (DOR) with no appreciable affinity for kappa (KOR) receptors in radioligand binding assays. The compound was found to be a mixed MOR agonist/partial DOR agonist in [(35)S]GTPγS functional assays, and it showed moderate analgesic potency in vivo. The compound showed no visible signs of physical dependence or constipation in mice. In addition, it produced less respiratory depression than morphine. Most mixed MOR/DOR opioids reported in the literature are peptides and thereby systemically inactive. Our approach utilizing a multicomponent reaction has the promise to deliver potent and efficacious small-molecule analgesics with potential clinical utility.


Assuntos
Analgésicos Opioides/síntese química , Analgésicos Opioides/farmacologia , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Amidas/síntese química , Amidas/química , Analgésicos Opioides/efeitos adversos , Analgésicos Opioides/química , Animais , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Fentanila/análogos & derivados , Fentanila/síntese química , Fentanila/química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Estrutura Molecular , Morfina/efeitos adversos , Morfina/química , Morfina/farmacologia , Dor/tratamento farmacológico , Respiração/efeitos dos fármacos
12.
Org Lett ; 16(6): 1668-71, 2014 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-24580074

RESUMO

The formation of an unexpected heterocyclic scaffold, a benzoxazole, in a three-component reaction between a ketone, isocyanide, and 2-aminophenol was encountered. This reaction involved a benzo[b][1,4]oxazine intermediate resulting from intramolecular attack of the aminophenol hydroxyl group on the nitrilium ion. Unlike previous literature examples, the trapped nitrilium benzo[b][1,4]oxazine could readily be subjected to ring opening with bis-nucleophiles. The reaction scope includes simple linear as well as complex cyclic ketones and substituted 2-aminophenols. A representative benzoxazole product could be further diversified to yield drug-like compounds.


Assuntos
Aminofenóis/química , Benzoxazóis/síntese química , Cetonas/química , Nitrilas/síntese química , Oxazinas/química , Benzoxazóis/química , Estrutura Molecular , Nitrilas/química , Estereoisomerismo
13.
J Med Chem ; 55(14): 6352-62, 2012 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-22734622

RESUMO

3-Iodobenzoylnaltrexamide 1 (IBNtxA) is a potent analgesic acting through a novel receptor target that lack many side-effects of traditional opiates composed, in part, of exon 11-associated truncated six transmembrane domain MOR-1 (6TM/E11) splice variants. To better understand the SAR of this drug target, a number of 4,5-epoxymorphinan analogues were synthesized. Results show the importance of a free 3-phenolic group, a phenyl ring at the 6 position, an iodine at the 3'or 4' position of the phenyl ring, and an N-allyl or c-propylmethyl group to maintain high 6TM/E11 affinity and activity. 3-Iodobenzoylnaloxamide 15 (IBNalA) with a N-allyl group displayed lower δ opioid receptor affinity than its naltrexamine analogue, was 10-fold more potent an analgesic than morphine, elicited no respiratory depression or physical dependence, and only limited inhibition of gastrointestinal transit. Thus, the aryl-naloxamide scaffold can generate a potent analgesic acting through the 6TM/E11 sites with advantageous side-effect profile and greater selectivity.


Assuntos
Amidas/síntese química , Amidas/farmacologia , Éxons/genética , Alcaloides Opiáceos/síntese química , Alcaloides Opiáceos/farmacologia , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Amidas/química , Amidas/metabolismo , Analgésicos/síntese química , Analgésicos/química , Analgésicos/metabolismo , Analgésicos/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Técnicas de Química Sintética , Masculino , Camundongos , Alcaloides Opiáceos/química , Alcaloides Opiáceos/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estrutura Terciária de Proteína , Receptores Opioides mu/química , Relação Estrutura-Atividade
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