Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Xu, Heng; Hashimoto, Akihiro; Rice, Kenner C.; Jacobson, Arthur E.; Thomas, James B.; Carroll, F. Ivy; Lai, Josephine; Rothman, Richard B.

doi:10.1002/1098-2396(20010101)39:1<64::aid-syn9>3.0.co;2-j

Cited by 31 publications

(45 citation statements)

References 22 publications

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“…Analogues 8-11 were then evaluated for affinity at opioid receptors using methodology previously described (Table 1). 21 As shown previously, 1 and 2 have approximately the same affinity and selectivity for κ receptors. 11 This indicated that perhaps chain length might not play an important role.…”

supporting

confidence: 68%

Synthesis of Salvinorin A Analogues as Opioid Receptor Probes

Tidgewell

Lozama

et al. 2006

J. Nat. Prod.

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Several neoclerodanes, such as salvinorin A (1) and herkinorin (3), have recently been shown to possess opioid receptor activity in vitro and in vivo. To explore the structure-affinity relationships of this interesting class of compounds, we have synthesized a series of analogues from 1 isolated from SalVia diVinorum. Here, we report the semisynthesis of neoclerodane diterpenes and their structure-affinity relationships at opioid receptors. This work will allow the further development of novel opioid receptor ligands.SalVia diVinorum is a plant from the mint family that has been used in the traditional spiritual practices by the Mazatec Indians of Oaxaca, Mexico. Chewing fresh leaves or smoking dried leaves will produce hallucinogenic-like experiences. 1 These experiences last for up to an hour and are reported to be potent and intense. [2][3][4][5] These effects, however, appear to be different than other hallucinogenic substances such as LSD or DOB. Recreational use of S. diVinourm is increasing in part due to its availability for purchase through the Internet. 6 The main active constituent isolated from the leaves of S. diVinorum is salvinorin A (1), a neoclerodane diterpene. 7,8 Compound 1 was found to be a potent and selective κ opioid receptor (κOR) agonist. 9-11 Interestingly, the pharmacology of 1 appears to be different than other κ agonists. 12 Recent work has shown that 1 decreases dopamine levels in the caudate putamen of mice and that this effect is blocked by the κOR antagonist nor-binaltorphimine. 13 A study has also shown that 1 dose dependently increases immobility in the forced swim test, indicating that 1 has depressivelike effects. 14 Furthermore, 1 disrupts climbing behavior on an inverted screen task. 15 This study showed that there are differences in the susceptibility of 1 and the standard κOR agonist U69,593 to antagonism by nor-binaltorphimine. This finding also indicates that 1 may bind in a manner that is qualitatively different than traditional κOR ligands.Recently, we described the synthesis of several analogues of 1 that were found to be opioid receptor ligands. 11 Among these compounds described were analogues 2-4. Propionate 2 was found to have approximately the same affinity for the κOR as 1 but was less potent as an agonist. This work also identified herkinorin (3), the first neoclerodane diterpene with µ opioid receptor affinity, and WH-1-32 (4), an analogue slightly more potent than 1 as a κOR agonist. 11 Recently, methoxymethyl analogue 5 16 and carbamate 6 17 were identified as having affinity for κORs similar to 1. Interestingly, 5 was found to be a full agonist more potent than 1, and 6 is a partial agonist at κORs. These observations illustrate that substitution at the C-2 position can have profound effects on opioid receptor affinity and activity.Recently, a model was proposed for the binding of 1 to the κOR. 18 This model was developed through the use of molecular modeling and mutagenesis studies. However, the binding pocket of salvinorin A will not be known until the ...

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confidence: 68%

Synthesis of Salvinorin A Analogues as Opioid Receptor Probes

Tidgewell

Lozama

et al. 2006

J. Nat. Prod.

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“…[ 35 S]GTP␥S binding was determined as described previously (Xu et al, 2001). In brief, test tubes received the following additions: 50 l of buffer A (50 mM Tris-HCl, pH 7.4, containing 100 mM NaCl, 10 mM MgCl 2 , and 1 mM EDTA), 50 l of GDP in buffer A (final concentration ϭ 50 M), 50 l of drug in buffer A/0.1% bovine serum albumin, 50 l of […”

Section: Methodsmentioning

confidence: 99%

Salvinorin A: Allosteric Interactions at the μ-Opioid Receptor

Rothman¹,

Murphy²,

Xu³

et al. 2006

J Pharmacol Exp Ther

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“…Binding of [ 35 S]GTP␥S (PerkinElmer Life Sciences) was determined as described previously (Xu et al, 2001) jpet.aspetjournals.org 0.1% bovine serum albumin. Incubations were conducted for 3 h at 25°C (steady state).…”

Section: Methodsmentioning

confidence: 99%

Neuropeptide Y Y4 Receptor Homodimers Dissociate upon Agonist Stimulation

Berglund¹,

Schober²,

Esterman³

et al. 2003

J Pharmacol Exp Ther

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The pancreatic polypeptide-fold family of peptides consists of three 36-amino acid peptides, namely neuropeptide Y (NPY), peptide YY, and pancreatic polypeptide (PP). These peptides regulate important functions, including food intake, circadian rhythms, mood, blood pressure, intestinal secretion, and gut motility, through four receptors: Y1, Y2, Y4, and Y5. Additional receptor subtypes have been proposed based on pharmacology observed in native tissues. Recent studies with other Gprotein-coupled receptors have shown that homo-and heterodimerization may be important in determining receptor function and pharmacology. In the present study, the recently cloned rhesus (rh) Y4 receptor was evaluated using radioligand binding, and the pharmacological profile was found to be very similar to the human Y4 receptor. To study homo-and heterodimerization involving the Y4 receptor using bioluminescence resonance energy transfer 2 (BRET 2 ), the carboxy termini of the rhesus Y1, Y2, Y4, and Y5 receptors were fused to Renilla luciferase, and rhY4 was also fused to green fluorescent protein. Dimerization was also studied using Western blot analysis. Using both BRET 2 and Western analysis, we found that the rhY4 receptor is present at the cell surface as a homodimer. Furthermore, agonist stimulation using the Y4-selective agonists PP and 1229U91 can dissociate these dimers in a concentration-dependent manner. In contrast, rhY4 did not heterodimerize with other members of the NPY receptor family or with human opioid ␦ and receptors. Therefore, homodimerization is an important component in the regulation of the Y4 receptor.The neuropeptide Y (NPY) family of peptides consists of NPY, peptide YY (PYY), and pancreatic polypeptide (PP). These peptides regulate many important physiological functions, such as energy homeostasis, mood, and blood pressure. Currently, there are four cloned functional G-protein-coupled receptors (GPCRs), namely Y1, Y2, Y4, and Y5, that make up the NPY receptor family (see Berglund et al., 2003a for a review) in most mammals. All of these receptor subtypes are found in the brain as well as peripheral tissues. In addition, rabbits and mice have a functional y6 receptor, whereas in primates, this receptor subtype is not functional. NPY, PYY, and PP share a similar rank order of potencies at the Y1, Y2, and Y5 receptors: NPY Ϸ PYY Ͼ PP, whereas the Y4 receptor binds PP with higher affinity than it binds NPY and PYY and is thus regarded as the PP receptor. Like PP, the Y4 receptor is mainly found in the gut (Lundell et al., 1995), but binding sites for PP and Y4 mRNA have also been found in several rat brain regions, including hypothalamus and brainstem (Berglund et al., 2003a), suggesting that PP may also have direct effects on brain function. Besides the cloned NPY receptor family, several additional receptor subtypes have been proposed based on pharmacological evaluation of various tissue preparations. However, the first draft of the human genome did not provide evidence for any additional NPY receptor...

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Opioid peptide receptor studies. 14. Stereochemistry determines agonist efficacy and intrinsic efficacy in the [35S]GTP-?-S functional binding assay

Cited by 31 publications

References 22 publications

Synthesis of Salvinorin A Analogues as Opioid Receptor Probes

Synthesis of Salvinorin A Analogues as Opioid Receptor Probes

Salvinorin A: Allosteric Interactions at the μ-Opioid Receptor

Neuropeptide Y Y4 Receptor Homodimers Dissociate upon Agonist Stimulation

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