Structure–activity relationship studies of dynorphin A and related peptides

Naqvi, Tahira; Haq, W.; Mathur, K. B.

doi:10.1016/s0196-9781(98)00042-4

Cited by 42 publications

(45 citation statements)

References 69 publications

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“…The previously described lead optimization work was strongly focused on KOR affinity and peptide stability optimization. To ensure that while improving activity, selectivity for KOR was not lost, we investigated selected key milestone molecules (1,6,23,26,39,44,48), where strong structural changes were made, for their receptor selectivity. The selectivity profile of dynA (1− 17) and selected peptides, e.g., 1, 6, 23, 26, 39, 44, 48 at other opiate receptors (Table 3) indicated that improvements in KOR affinity paralleled improvements in KOR selectivity relative to MOR, DOR, and NOP.…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

et al. 2016

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Opioid receptor screening of a conopeptide library led to a novel selective κ-opioid agonist peptide (conorphin T). Intensive medicinal chemistry, guided by potency, selectivity, and stability assays generated a pharmacophore model supporting rational design of highly potent and selective κ-opioid receptor (KOR) agonists (conorphins) with exceptional plasma stability. Conorphins are defined by a hydrophobic benzoprolyl moiety, a double arginine sequence, a spacer amino acid followed by a hydrophobic residue and a C-terminal vicinal disulfide moiety. The pharmacophore model was supported by computational docking studies, revealing receptor−ligand interactions similar to KOR agonist dynorphin A (1−8). A conorphin agonist inhibited colonic nociceptors in a mouse tissue model of chronic visceral hypersensitivity, suggesting the potential of KOR agonists for the treatment of chronic abdominal pain. This new conorphine KOR agonist class and pharmacophore model provide opportunities for future rational drug development and probes for exploring the role of the κ-opioid receptor.

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Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

et al. 2016

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“…The truncated analog retains the potency and selectivity (32) of the parent peptide while containing the message (residues 1-5) and a portion of the highly positively charged address C terminus (residues 6 -8) (22,29).…”

Section: Prediction Of a Putative Binding Mode For Dynorphin A(1-8)-dmentioning

confidence: 99%

Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

Vardy

Mosier

Frankowski

et al. 2013

Journal of Biological Chemistry

140

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Background:The -opioid receptor can be activated by structurally diverse agonists. Results: Four structurally diverse agonists differentially bound to and activated wild type and mutant -opioid receptors. Conclusion:The structural features of the agonists dictate how they interact with and stabilize G i -signaling receptor conformations. Significance: The results provide insights into the structural basis of opioid receptor ligand recognition and activation.

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“…Prodynorphin is the precursor of leucine-enkephalin, dynorphin A and B, and ␣-neoendorphin (Civelli et al, 1985;Day et al, 1998). These peptides participate in a wide variety of physiologic functions including reproduction, cardiovascular regulation, water balance, and thermoregulation (Leadem and Kalra, 1985;Smith and Lee, 1988;Smith and Gallo, 1997;Naqvi et al, 1998;Zhang and Gallo, 2003;Goodman et al, 2004). In the ewe, dynorphin neurons express the progesterone receptor, and there is compelling evidence that dynorphin mediates progesterone feedback on pulsatile LH secretion (Foradori et al, 2002;Goodman et al, 2004).…”

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confidence: 99%

Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus

Burke

Letts

Krajewski

et al. 2006

J of Comparative Neurology

252

250

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Considerable evidence suggests that dynorphin and neurokinin B (NKB) neurons in the hypothalamic arcuate nucleus participate in the sex-steroid regulation of reproduction. In the present study, we used dual-label immunofluorescence to explore the distribution of prodynorphin and proNKB immunoreactivity in the rat hypothalamus. Additionally, we investigated whether arcuate prodynorphin-ir (immunoreactive) neurons expressed the neurokinin 3 receptor (NK3R) or nuclear estrogen receptor-alpha (ERalpha). We found that the majority of prodynorphin-ir neurons in the rat arcuate nucleus expressed proNKB, whereas nearly all (99%) of the proNKB neurons were immunoreactive for prodynorphin. The arcuate nucleus was the only site in the hypothalamus where neuronal somata coexpressing prodynorphin and proNKB-immunoreactivity were identified. A dense plexus of double-labeled prodynorphin/proNKB-ir fibers was found within the arcuate nucleus extending to the median eminence and throughout the periventricular zone of the hypothalamus. Prodynorphin/proNKB fibers were also identified in the paraventricular nucleus, anterior hypothalamic area, medial preoptic area, median preoptic nucleus, anteroventral periventricular nucleus, and bed nucleus of the stria terminalis in a distribution consistent with previously described arcuate nucleus projections. Interestingly, the majority of prodynorphin-ir neurons in the arcuate nucleus expressed NK3R, and nearly 100% of the prodynorphin-ir neurons contained nuclear ERalpha. Our results suggest that there is a close functional relationship between dynorphin and NKB peptides within the arcuate nucleus of the rat, which may include an autofeedback loop mediated through NK3R. The diverse hypothalamic projections of fibers expressing both prodynorphin and proNKB provide evidence that these neurons may participate in a variety of homeostatic and neuroendocrine processes.

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Structure–activity relationship studies of dynorphin A and related peptides

Cited by 42 publications

References 69 publications

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

Conopeptide-Derived κ-Opioid Agonists (Conorphins): Potent, Selective, and Metabolic Stable Dynorphin A Mimetics with Antinociceptive Properties

Chemotype-selective Modes of Action of κ-Opioid Receptor Agonists

Coexpression of dynorphin and neurokinin B immunoreactivity in the rat hypothalamus: Morphologic evidence of interrelated function within the arcuate nucleus

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