Further Studies on the Dmt-Tic Pharmacophore:  Hydrophobic Substituents at the C-Terminus Endow δ Antagonists To Manifest μ Agonism or μ Antagonism

Salvadori, Severo; Guerrini, Remo; Balboni, Gianfranco; Bianchi, Clementina; Bryant, Sharon D.; Cooper, P. S.; Lazarus, Lawrence H.

doi:10.1021/jm990165m

Cited by 69 publications

(87 citation statements)

References 58 publications

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“…56 The benzylamide peptide, H-Dmt-Tic-Gly-NH-CH 2 -Ph, was also found to be a potent agonist (pEC 50 = 8.57) and ␦ antagonist (pA2 = 9.25) in the smooth muscle assays. 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.…”

Section: E122mentioning

confidence: 97%

“…55 Among N-and C-modifi ed Dmt-Tic analogs, the N,N-dimethylated adamantylamide, N,N -(Me 2 )Dmt-Tic-NH-1-adamantane, was found to display high affi nity binding to ␦ and receptors ( K i at ␦ = 0.16 nM, K i at = 1.12 nM) with potent ␦ antagonist (pA 2 = 9.06 in MVD) and agonist (IC 50 = 16 nM in GPI) activities. 56 The benzylamide peptide, H-Dmt-Tic-Gly-NH-CH 2 -Ph, was also found to be a potent agonist (pEC 50 = 8.57) and ␦ antagonist (pA2 = 9.25) in the smooth muscle assays. 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.…”

Section: Peptide Ligands Possessing Mixed Agonist/ ␦ Antagonist Activitymentioning

confidence: 97%

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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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Section: E122mentioning

confidence: 97%

Section: Peptide Ligands Possessing Mixed Agonist/ ␦ Antagonist Activitymentioning

confidence: 97%

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

Ananthan

2006

AAPS J

126

110

View full text Add to dashboard Cite

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“…The dipeptide analog H-Dmt-Tic-NH-(CH 2 ) 3 -Ph is also a potent MOPr agonist/DOPr antagonist with subnanomolar MOPr and DOPr binding affinities. Subsequently, the dipeptide derivative Dmt(NMe 2 )-Tic-NH-1-adamantane (Salvadori et al, 1999) and the tripeptide analog H-Dmt-Tic-Gly-NH-CH 2 -Ph (Balboni et al, 2002a) were also reported to be potent MOPr agonists/DOPr antagonists. .…”

Section: Mixed M-opioid Receptor Agonists/d-opioid Receptor Antagomentioning

confidence: 99%

Molecular Pharmacology of δ-Opioid Receptors

Gendron

Cahill

Zastrow

et al. 2016

Pharmacological Reviews

109

108

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“…Tic-deltorphin was obtained by solid-phase synthesis carried out on an Applied Biosystems 433A peptide synthesizer by using 9-fluorenylmethoxycarbonyl chemistry. N,N-(CH3) 2 -Dmt-Tic-NH 2 was synthesized as reported in Salvadori et al (1999). All materials for tissue culture were supplied by Invitrogen (Paisley, UK).…”

mentioning

confidence: 99%

μ-δ Opioid Receptor Functional Interaction: Insight Using Receptor-G Protein Fusions

Snook¹,

Milligan²,

Kieffer³

et al. 2006

The Journal of Pharmacology and Experimental Therapeutics

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Fusion proteins between a receptor and a pertussis toxininsensitive G i ␣ subunit were used to gain insight into the molecular interactions that take place upon and ␦ opioid receptor heterodimerization. When opioid receptor-G i1 ␣ fusions were coexpressed with nonfused ␦ opioid receptors in human embryonic kidney 293 cells, or vice versa, receptor heterodimers were detected by coimmunoprecipitation. In pertussis toxin-treated cells, receptor coexpression decreased the amount of guanosine 5Ј-O-(3-[35 S]thio)triphosphate ([ 35 S]GTP␥S) incorporated in the fused G␣ protein after the addition of agonists specific for the receptor-G i1 ␣ fusion. In addition, activation of the G␣ protein occurred in heterodimers upon addition of an agonist specific for the nonfused receptor.It remained unaffected by an inverse agonist specific for the receptor-G i1 ␣ fusion. These data suggest that signaling through the receptor-G i1 ␣ fusion protein is impaired in heterodimers and support a mechanism in which activation of the G␣ subunit is promoted by a direct interaction with the nonfused receptor. Alternatively, receptor coexpression did not modify the ligand binding properties for the high-affinity state of the receptor-G i1 ␣ fusion nor the EC 50 values for agonist-induced [35 S]GTP␥S incorporation in the G i1 ␣ subunit. In addition, no binding competition was observed between ␦ and ligands. Together, the data point to -␦ opioid receptor heterodimers formed by contact interactions between monomers that retain their structural integrity.Genes coding for ␦, , and opioid receptor types have been identified and isolated from different vertebrates and belong to the G protein-coupled receptor (GPCR) superfamily. The opioid receptors and endogenous opioid peptides form a neuromodulatory system that plays a major role in the control of nociceptive pathways. The opioid system also modulates affective behavior, neuroendocrine physiology, and controls autonomic functions such as respiration, blood pressure, thermoregulation, and gastrointestinal motility. Importantly, the receptors are targets for exogenous narcotic opiate alkaloids that constitute a major class of drugs of abuse (Massotte and Kieffer, 1998;Bodnar and Hadjimarkou, 2003).GPCR signaling is a complex process whose modulation likely proceeds from many intricate factors. Recently, a possible involvement of the receptor oligomerization state has received growing attention since existence of homo-and heterodimers has been postulated for an increasing number of GPCRs (for reviews, see Milligan, 2004;Park et al., 2004;Prinster et al., 2005). Arguments in favor of a spatial proximity between receptor molecules mainly arose from coimmunoprecipitation studies and more recently from bioluminescence and fluorescence resonance energy transfer experiments (for review, see Milligan and Bouvier, 2005). However, establishing physical proximity between receptors does not necessarily imply functional interactions between them. Even when modifications of the signaling properties seemed ...

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Further Studies on the Dmt-Tic Pharmacophore: Hydrophobic Substituents at the C-Terminus Endow δ Antagonists To Manifest μ Agonism or μ Antagonism

Cited by 69 publications

References 58 publications

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

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

Molecular Pharmacology of δ-Opioid Receptors

μ-δ Opioid Receptor Functional Interaction: Insight Using Receptor-G Protein Fusions

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