Potent δ-Opioid Receptor Agonists Containing the Dmt−Tic Pharmacophore

Balboni, Gianfranco; Salvadori, Severo; Guerrini, Remo; Negri, Lucia; Giannini, Elisa; Jinsmaa, Yunden; Bryant, Sharon D.; Lazarus, Lawrence H.

doi:10.1021/jm020336e

Cited by 85 publications

(131 citation statements)

References 41 publications

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“…Surprisingly, compound 4 shows μ agonist activity comparable to the reference, accomplished by a weak δ agonist activity; its behaviour is reversed in comparison with the reference. Finally, compounds 5 and 6 containing the imidazole heterocycle with (5) or without a phenyl ring (6), are characterized by a completely different behaviour; in fact the presence of the phenyl ring induces a potent antagonist activity (5) while its absence (6) . Ninhydrin (1% ethanol, Merck), fluorescamine (Hoffman-La Roche) and chlorine spray reagents.…”

Section: Resultsmentioning

confidence: 99%

“…Pseudopeptides (1)(2)(3)(4)(5)(6) were prepared in solution by peptide synthetic methods. Simply, BocDmt-Tic-OH 19 was coupled with H 2 N-CH 2 -hetero-/homo-cycle via WSC/HOBt.…”

Section: Chemistrymentioning

confidence: 99%

“…Simply, BocDmt-Tic-OH 19 was coupled with H 2 N-CH 2 -hetero-/homo-cycle via WSC/HOBt. Final Nterminal Boc deprotection with TFA and purification by preparative HPLC, gave compounds (1)(2)(3)(4)(5)(6). The intermediates (benzo [d]oxazol-2-yl)methanamine (H 2 N-CH 2 -Boa) and (benzo [d] thiazol-2-yl)methanamine (H 2 N-CH 2 -Bta) were prepared according to the procedure of Nestor et al 13 Mixed carbonic anhydride coupling of Z-Gly-OH with o-aminophenol gave the crude intermediate amide, which was converted without purification to the desired benzoxazole (Z-NH-CH 2 -Boa) by cyclization and dehydration in refluxing propionic acid (~140°C).…”

Section: Chemistrymentioning

confidence: 99%

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Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Salvadori

Fiorini

Trapella

et al. 2008

Bioorganic & Medicinal Chemistry

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H-Dmt-Tic-NH-CH 2 -Bid (UFP-502) was the first δ opioid agonist prepared from the Dmt-Tic pharmacophore. It showed interesting pharmacological properties, such as stimulation of mRNA BDNF expression, and antidepression. To evaluate the importance of 1H-benzimidazol-2-yl (Bid) in the induction of δ agonism, it was substituted by similar heterocycles: The substitution of NH (1) by O or S, transforms the reference δ agonist into δ antagonists. Phenyl ring of benzimidazole is not important for δ agonism; in fact 1H-imidazole-2-yl retains δ agonist activity.

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Section: Resultsmentioning

confidence: 99%

“…Pseudopeptides (1)(2)(3)(4)(5)(6) were prepared in solution by peptide synthetic methods. Simply, BocDmt-Tic-OH 19 was coupled with H 2 N-CH 2 -hetero-/homo-cycle via WSC/HOBt.…”

Section: Chemistrymentioning

confidence: 99%

Section: Chemistrymentioning

confidence: 99%

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Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Salvadori

Fiorini

Trapella

et al. 2008

Bioorganic & Medicinal Chemistry

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“…This suggests that MOR plays little, if any, role in the DOR agonistinduced effect. If MOR were critically involved in the effect seen in our first set of experiments, we would have expected to see a major increase in the protection induced by increased H-Dmt-Tic-NH-CH(CH2-COOH)-Bid, as it has a very low affinity for MOR (Balboni et al, 2002). In fact, there is evidence showing that MOR activation aggravates neurotoxic effects of hypoxia/hypoglycemia, induces apoptosis of human neurons and microglia, and inhibits neuronal survival in the mouse (Ammon-Treiber et al, 2005;Hu et al, 2002;Hauser et al, 1994).…”

Section: L) (E-h)mentioning

confidence: 94%

Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

Chao

Donnelly

Yin

et al. 2006

J Cereb Blood Flow Metab

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Central neurons are extremely vulnerable to hypoxic/ischemic insult, which is a major cause of neurologic morbidity and mortality as a consequence of neuronal dysfunction and death. Our recent work has shown that d-opioid receptor (DOR) is neuroprotective against hypoxic and excitotoxic stress, although the underlying mechanisms remain unclear. Because hypoxia/ischemia disrupts ionic homeostasis with an increase in extracellular K + , which plays a role in neuronal death, we asked whether DOR activation preserves K + homeostasis during hypoxic/ischemic stress. To test this hypothesis, extracellular recordings with K + -sensitive microelectrodes were performed in mouse cortical slices under anoxia or oxygen-glucose deprivation (OGD). The main findings in this study are that (1) DOR activation with [D-Ala 2 , D-Leu 5 ]-enkephalinamide attenuated the anoxia-and OGD-induced increase in extracellular K + and decrease in DC potential in cortical slices; (2) DOR inhibition with naltrindole, a DOR antagonist, completely abolished the DOR-mediated prevention of increase in extracellular K + and decrease in DC potential; (3) inhibition of protein kinase A (PKA) with N-(2-[p-bromocinnamylamino]-ethyl)-5-isoquinolinesulfonamide dihydrochloride had no effect on the DOR protection; and (4) inhibition of protein kinase C (PKC) with chelerythrine chloride reduced the DOR protection, whereas the PKC activator (phorbol 12-myristate 13-acetate) mimicked the effect of DOR activation on K + homeostasis. These data suggest that activation of DOR protects the cortex against anoxia-or ODG-induced derangement of potassium homeostasis, and this protection occurs via a PKC-dependent and PKA-independent pathway. We conclude that an important aspect of DOR-mediated neuroprotection is its early action against derangement of K + homeostasis during anoxia or ischemia.

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“…28 The heteroaryl analog, H-Dmt-Tic-NH-CH 2 -Bid (Bid = 1 H -benzimidazole-2-yl) similarly displayed potent ␦ antagonist activity coupled with weak agonist activity. 57 Nonpeptide ligands possessing mixed agonist/ ␦ antagonist activity…”

Section: Peptide Ligands Possessing Mixed Agonist/ ␦ Antagonist Activitymentioning

confidence: 99%

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Ananthan

2006

AAPS J

126

110

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A BSTRACTOpioids are widely used in the treatment of severe pain. The clinical use of the opioids is limited by serious side effects such as respiratory depression, constipation, development of tolerance, and physical dependence and addiction liabilities. Most of the currently available opioid analgesics exert their analgesic and adverse effects primarily through the opioid receptors. A large number of biochemical and pharmacological studies and studies using genetically modifi ed animals have provided convincing evidence regarding the existence of modulatory interactions between opioid and ␦ receptors. Several studies indicate that ␦ receptor agonists as well as ␦ receptor antagonists can provide benefi cial modulation to the pharmacological effects of agonists. For example, ␦ agonists can enhance the analgesic potency and effi cacy of agonists, and ␦ antagonists can prevent or diminish the development of tolerance and physical dependence by agonists. On the basis of these observations, the development of new opioid ligands possessing mixed agonist/ ␦ agonist profi le and mixed agonist/ ␦ antagonist profi le has emerged as a promising new approach to analgesic drug development. A brief overview of -␦ interactions and recent developments in identifi cation of ligands possessing mixed agonist/ ␦ agonist and agonist/ ␦ antagonist activities is provided in this report. K EYWORDS:Analgesics , Opioid Ligands , Mixed Mu/Delta agonists , Mixed Mu agonist/Delta antagonists , Peptides , Nonpeptides INTRODUCTIONOpioid analgesics are the standard therapeutic agents for the treatment of moderate-to-severe pain. These drugs exert their analgesic activity through their interaction with the opioid , ␦ , or receptors as agonists. The clinical usefulness of opioid agonists such as morphine, however, is limited by signifi cant side effects such as respiratory depression, constipation, development of tolerance and physical dependence, and addiction potential. One approach to limit -receptor-mediated side effects is to selectively target ␦ and opioid receptors. This approach has been explored using agonist ligands selective for ␦ and opioid receptors but has seen only limited success. The ␦ agonists generally display limited analgesic effi cacy and receptor agonists are limited to their use as peripheral analgesics owing to their psychotomimetic and dysphoric central effects. An alternative approach that is gaining considerable interest is the development of compounds that possess mixed opioid activity at the different opioid receptors. 1 , 2 Several lines of evidence indicate the existence of physical and functional interactions between the opioid receptors, particularly between the and ␦ receptors. Several biochemical and pharmacological studies using and ␦ receptor ligands gave an early indication of such interactions between the and ␦ receptors. [3][4][5][6] The and ␦ opioid receptors exist on overlapping populations of neurons in painmodulating regions of the central nervous system, and the presence of both and ␦ receptors ...

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Potent δ-Opioid Receptor Agonists Containing the Dmt−Tic Pharmacophore

Cited by 85 publications

References 41 publications

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

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Potent δ-Opioid Receptor Agonists Containing the Dmt−Tic Pharmacophore

Cited by 85 publications

References 41 publications

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Cortical δ-Opioid Receptors Potentiate K+ Homeostasis During Anoxia and Oxygen–Glucose Deprivation

Opioid ligands with mixed μ/δ opioid receptor interactions: An emerging approach to novel analgesics

Contact Info

Product

Resources

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Cortical δ-Opioid Receptors Potentiate K⁺ Homeostasis During Anoxia and Oxygen–Glucose Deprivation