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Thomas E Prisinzano - One of the best experts on this subject based on the ideXlab platform.
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Unconditioned BehAviorAl Effects of the Powerful -Opioid HAllucinogen SAlvinorin A in NonhumAn PrimAtes: FAst Onset And Entry into CerebrospinAl Fluid
2020Co-Authors: Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng, Szymon Rus, Mary Jeanne KreekAbstract:ABSTRACT SAlvinorin A is the mAin Active component of the widely AvAilAble hAllucinogenic plAnt, SAlviA divinorum. SAlvinorin A is A selective high-efficAcy -Agonist in vitro, with some unique phArmAcodynAmic properties. Descriptive reports show thAt SAlvinorin A-contAining products produce robust behAviorAl effects in humAns. However, these effects hAve not been systemAticAlly chArActerized in humAn or nonhumAn primAtes to dAte. Therefore, the present studies focused on the chArActerizAtion of overt effects of SAlvinorin A, such As sedAtion (operAtionAlly defined As unresponsiveness to environmentAl stimuli) And posturAl relAxAtion, previously observed with centrAlly penetrAting -Agonists in nonhumAn primAtes. SAlvinorin A wAs Active in these endpoints (dose rAnge, 0.01-
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Addressing structurAl flexibility At the A ring on SAlvinorin A discovery of A potent kAppA opioid Agonist with enhAnced metAbolic stAbility
Journal of Medicinal Chemistry, 2017Co-Authors: Alexander M Sherwood, Victor W. Day, Bronwyn M Kivell, Rachel Saylor Crowley, Kelly F Paton, Andrew Biggerstaff, Benjamin Neuenswander, Thomas E PrisinzanoAbstract:Previous structure–Activity studies on the neoclerodAne diterpenoid SAlvinorin A hAve demonstrAted the importAnce of the Acetoxy functionAlity on the A-ring in its Activity As A κ-opioid receptor Agonist. Few studies hAve focused on understAnding the role of conformAtion in these interActions. Herein we describe the synthesis And evAluAtion of both flexible And conformAtionAlly restricted compounds derived from SAlvinorin A. One such compound, spirobutyrolActone 14, wAs synthesized in A single step from SAlvinorin B And hAd similAr potency And selectivity to SAlvinorin A (EC50 = 0.6 ± 0.2 nM At κ; >10000 nM At μ And δ). MicrosomAl stAbility studies demonstrAted thAt 14 wAs more metAbolicAlly resistAnt thAn SAlvinorin A. EvAluAtion of AnAlgesic And Anti-inflAmmAtory properties reveAled similAr in vivo effects between 14 And SAlvinorin A. To our knowledge, this study represents the first exAmple of bioisosteric replAcement of An AcetAte group by A spirobutyrolActone to produce A metAbolicAlly resistAnt deri...
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Addressing StructurAl Flexibility At the A‑Ring on SAlvinorin A: Discovery of A Potent KAppA-Opioid Agonist with EnhAnced MetAbolic StAbility
2017Co-Authors: Alexander M Sherwood, Victor W. Day, Bronwyn M Kivell, Rachel Saylor Crowley, Kelly F Paton, Andrew Biggerstaff, Benjamin Neuenswander, Thomas E PrisinzanoAbstract:Previous structure–Activity studies on the neoclerodAne diterpenoid SAlvinorin A hAve demonstrAted the importAnce of the Acetoxy functionAlity on the A-ring in its Activity As A κ-opioid receptor Agonist. Few studies hAve focused on understAnding the role of conformAtion in these interActions. Herein we describe the synthesis And evAluAtion of both flexible And conformAtionAlly restricted compounds derived from SAlvinorin A. One such compound, spirobutyrolActone 14, wAs synthesized in A single step from SAlvinorin B And hAd similAr potency And selectivity to SAlvinorin A (EC50 = 0.6 ± 0.2 nM At κ; >10000 nM At μ And δ). MicrosomAl stAbility studies demonstrAted thAt 14 wAs more metAbolicAlly resistAnt thAn SAlvinorin A. EvAluAtion of AnAlgesic And Anti-inflAmmAtory properties reveAled similAr in vivo effects between 14 And SAlvinorin A. To our knowledge, this study represents the first exAmple of bioisosteric replAcement of An AcetAte group by A spirobutyrolActone to produce A metAbolicAlly resistAnt derivAtive
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time course of phArmAcokinetic And hormonAl effects of inhAled high dose SAlvinorin A in humAns
Journal of Psychopharmacology, 2016Co-Authors: Matthew W. Johnson, Katherine A Maclean, Thomas E Prisinzano, Michael J. Caspers, Roland R GriffithsAbstract:SAlvinorin A is A kAppA opioid Agonist And the principAl psychoActive constituent of the SAlviA divinorum plAnt, which hAs been used for hAllucinogenic effects. Previous reseArch on SAlvinorin A phArmAcokinetics likely underestimAted plAsmA levels typicAlly resulting from the doses Administered due to inefficient vAporizAtion And not collecting sAmples during peAk drug effects. Six heAlthy Adults inhAled A single high dose of vAporized SAlvinorin A (n = 4, 21 mcg/kg; n = 2, 18 mcg/kg). PArticipAnt- And monitor-rAted effects were Assessed every 2 min for 60 min post-inhAlAtion. Blood sAmples were collected At 13 time points up to 90 min post-inhAlAtion. Drug levels peAked At 2 min And then rApidly decreAsed. Drug levels were significAntly, positively correlAted with pArticipAnt And monitor drug effect rAtings. SignificAnt elevAtions in prolActin were observed beginning 5 min post-inhAlAtion And peAking At 15 min post-inhAlAtion. Cortisol showed inconsistent increAses Across pArticipAnts. HormonAl responses were not well correlAted with drug levels. This is the first study to demonstrAte A direct relAtionship between chAnges in plAsmA levels of SAlvinorin A And drug effects in humAns. The results confirm the efficAcy of An inhAlAtion technique for SAlvinorin A.
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Synthesis And κ‑Opioid Receptor Activity of FurAn-Substituted SAlvinorin A AnAlogues
2015Co-Authors: Andrew P. Riley, Bronwyn M Kivell, Chad E. Groer, David Young, Amy W. Ewald, Thomas E PrisinzanoAbstract:The neoclerodAne diterpene SAlvinorin A, found in the leAves of SAlviA divinorum, is A potent κ-opioid receptor Agonist, mAking it An AttrActive scAffold for development into A treAtment for substAnce Abuse. Although severAl successful semisynthetic studies hAve been performed to elucidAte structure–Activity relAtionships, the lAck of AnAlogues with substitutions to the furAn ring of SAlvinorin A hAs prevented A thorough understAnding of its role in binding to the κ-opioid receptor. Herein we report the synthesis of severAl SAlvinorin A derivAtives with modified furAn rings. EvAluAtion of these compounds in A functionAl AssAy indicAted thAt stericAlly less demAnding substitutions Are preferred, suggesting the furAn ring is bound in A congested portion of the binding pocket. The most potent of the AnAlogues successfully reduced drug-seeking behAvior in An AnimAl model of drug-relApse without producing the sedAtion observed with other κ-opioid Agonists
Bruce M Cohen - One of the best experts on this subject based on the ideXlab platform.
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differentiAl signAling properties At the kAppA opioid receptor of 12 epi SAlvinorin A And its AnAlogues
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Cecile Beguin, Leeyuan Liuchen, William A Carlezon, Chad E. Groer, Justin S Potuzak, John M Streicher, Laura M Bohn, Bruce M CohenAbstract:The kAppA opioid receptor (KOPR) hAs been identified As A potentiAl drug tArget to prevent or Alter the course of mood, Anxiety And Addictive disorders or reduce response to stress. In A seArch for highly potent And selective KOPR pArtiAl Agonists As phArmAcologicAl tools, we hAve modified 12-epi-SAlvinorin A, A compound which we hAve previously observed to be A KOPR pArtiAl Agonist. Five AnAlogues of 12-epi-SAlvinorin A were synthesized And their effects on G protein ActivAtion As well As β-Arrestin2 recruitment were evAluAted. Only 12-epi-SAlvinorin A (1) pArtiAlly ActivAted signAling through G proteins, yet Acted As A full Agonist in the β-Arrestin 2 DiscoveRx AssAy. Other SAlvinorin AnAlogues tested in these functionAl AssAys were full Agonists in both AssAys of KOPR ActivAtion. By compArison, the non-selective opioid ligAnd nAlbuphine, known to be A pArtiAl Agonist for G-protein ActivAtion, wAs Also A pArtiAl Agonist for the β-Arrestin mediAted signAling pAthwAy ActivAted through KOPR.
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modificAtion of the furAn ring of SAlvinorin A identificAtion of A selective pArtiAl Agonist At the kAppA opioid receptor
Bioorganic & Medicinal Chemistry, 2009Co-Authors: Cecile Beguin, Leeyuan Liuchen, William A Carlezon, Bruce M Cohen, Katharine K Duncan, Thomas A MunroAbstract:In An effort to find novel Agents which selectively tArget the kAppA opioid receptor (KOPR), we modified the furAn ring of the highly potent And selective KOPR Agonist SAlvinorin A. Introduction of smAll substituents At C-16 wAs well tolerAted. 12-epi-SAlvinorin A, synthesized in four steps from SAlvinorin A, wAs A selective pArtiAl Agonist At the KOPR. No cleAr SAR pAtterns were observed for C-13 Aryl ketones. Introducing A hydroxymethylene group between C-12 And the furAn ring wAs tolerAted. SmAll C-13 esters And ethers gAve weAk KOPR Agonists, while All C-13 Amides were inActive. FinAlly, substitution of oxAdiAzoles for the furAn ring Abolished Affinity for the KOPR. None of the compounds displAyed Any KOPR AntAgonism or Any Affinity for mu or deltA opioid receptors.
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synthesis And in vitro phArmAcologicAl studies of new c 4 modified SAlvinorin A AnAlogues
Bioorganic & Medicinal Chemistry Letters, 2006Co-Authors: David Y W Lee, Leeyuan Liuchen, Yulin Wang, William A Carlezon, Bruce M CohenAbstract:AbstrAct SAlvinorin A, A compound isolAted from the plAnt SAlviA divinorum, is A potent And highly selective Agonist for the κ opioid receptor. For explorAtion of its structure And Activity relAtionships, further modificAtions, such As reduction At the C(4) position, hAve been studied And A series of SAlvinorin A derivAtives were prepAred. These C(4)-modified SAlvinorin A AnAlogues were screened for binding And functionAl Activities At the humAn κ-opioid receptor And severAl new full Agonists hAve been identified.
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synthesis And in vitro phArmAcologicAl studies of c 4 modified SAlvinorin A AnAlogues
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: David Y W Lee, Leeyuan Liuchen, Leelakrishna Kondaveti, Yulin Wang, Yong Chen, Cecile Beguin, William A Carlezon, Bruce M CohenAbstract:SAlvinorin A is the most potent nAturAlly occurring opioid Agonist with A high selectivity And Affinity for kAppA-opioid receptor. To explore its structure-Activity relAtionships, modificAtions At the C(4) position hAve been studied And A series of SAlvinorin A derivAtives were prepAred. These C(4)-modified SAlvinorin A AnAlogues were screened for binding And functionAl Activities At the humAn kAppA-opioid receptor And severAl potent new Agonists hAve been identified.
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synthesis And in vitro phArmAcologicAl studies of new c 2 modified SAlvinorin A AnAlogues
Bioorganic & Medicinal Chemistry Letters, 2005Co-Authors: David Y W Lee, Vishnu Vardhan R Karnati, Leeyuan Liuchen, Leelakrishna Kondaveti, Yulin Wang, Yong Chen, Cecile Beguin, William A Carlezon, Bruce M CohenAbstract:AbstrAct SAlvinorin A is the most potent nAturAlly occurring opioid Agonist yet discovered with high selectivity And Affinity for κ-opioid receptor. To explore its structure And Activity relAtionships, A series of SAlvinorin A derivAtives modified At the C(2) position were prepAred And studied. These SAlvinorin A derivAtives were screened for binding And functionAl Activities At the humAn κ-opioid receptor. Compound 4, contAining A methoxymethyl group At the 2-position, wAs A full κ-Agonist with An EC50 vAlue At 0.6 nM, which is About 7 times more potent thAn SAlvinorin A.
Renyu Liu - One of the best experts on this subject based on the ideXlab platform.
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intrAnAsAl SAlvinorin A improves neurologicAl outcome in rhesus monkey ischemic stroke model using Autologous blood clot
Journal of Cerebral Blood Flow and Metabolism, 2021Co-Authors: Jian Chen, Chunhua Chen, Tianqi Yao, Xinglong Zhi, Renyu LiuAbstract:SAlvinorin A (SA) exerts neuroprotection And improves neurologicAl outcomes in ischemic stroke models in rodents. In this study, we investigAted whether intrAnAsAl SA AdministrAtion could improve n...
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effects of plAnt derived AnAlgesic compounds sinomenine And SAlvinorin A in infAnt rAts
Journal of Integrative Medicine, 2020Co-Authors: Conrad J Mascarenhas, Renyu Liu, Gordon A BarrAbstract:AbstrAct Objective PremAture And ill neonAtes undergo pAinful but medicAlly necessAry procedures while hospitAlized. Although opiAte drugs Are Administered As AnAlgesics, problems AssociAted with their side effects, tolerAnce, And potentiAl dependence necessitAte reseArch into AlternAtive pAin-relieving medicAtions. Here we test two plAnt-derived compounds in infAnt rAts: sinomenine, which tArgets the MAs-relAted G-protein-coupled receptor member X2 opioid receptor; And SAlvinorin A, which is A κ opioid receptor Agonist. In Adult AnimAls both sinomenine And SAlvinorin A Are AnAlgesic, but neither hAs been tested in infAnts. Methods We used the formAlin And thermAl plAntAr tests in rAts 7 And 21 dAys of Age (PN7 And PN21) for behAviorAl signs of pAin. In Addition, brAin sections were stAined using Fos immunohistochemistry to exAmine pAtterns of brAin ActivAtion in the midbrAin periAqueductAl grAy And the pArAventriculAr nucleus of the hypothAlAmus. Results Sinomenine wAs AnAlgesic in both the formAlin And thermAl tests on AnimAls 21 dAys of Age. At PN7 only the highest dose elevAted response lAtencies in the thermAl test And there were no effects of sinomenine in the formAlin test. AnAlysis of Fos expression in the sinomenine-treAted AnimAls showed no drug effect, in contrAst to the behAviorAl results. SAlvinorin A wAs AnAlgesic in the formAlin test only At the highest dose At 21 dAys of Age but not in the thermAl test At either Age. Conclusion The increAsed modest effectiveness of sinomenine in older AnimAls And the minimum SAlvinorin A drug effect suggest thAt the compounds Act on sites thAt develop during the preweAning period (sinomenine) or After weAning (SAlvinorin A).
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SAlvinorin A AmeliorAtes cerebrAl vAsospAsm through ActivAtion of endotheliAl nitric oxide synthAse in A rAt model of subArAchnoid hemorrhAge
Microcirculation, 2018Co-Authors: Juan Sun, Renyu Liu, Yan Zhang, Weiguang Zhang, Junhao Yan, Lei Yang, Changman Zhou, Chunhua ChenAbstract:Objective This study Aimed to demonstrAte the potentiAl of SAlvinorin A (SA) for cerebrAl vAsospAsm After subArAchnoid hemorrhAge (SAH) And investigAte mechAnisms of therApeutic effect using rAt SAH model. Methods SAlvinorin A wAs injected intrAperitoneAlly, And the neurobehAviorAl chAnges were observed At 12 hours, 24 hours, 48 hours, And 72 hours After SAH. BAsilAr Artery wAs observed by mAgnetic resonAnce imAging (MRI). The inner diAmeter And thickness of bAsilAr Artery were meAsured. The morphologicAl chAnges And the Apoptosis in CA1 AreA of hippocAmpus were detected. Endothelin-1 (ET-1) And nitric oxide (NO) levels were detected by ELISA kit. The protein expression of endotheliAl NO synthAse (eNOS) And AquAporin-4 (AQP-4) wAs determined by Western blot for potentiAl mechAnism explorAtion. Results SAlvinorin A AdministrAtion could relieve neurologicAl deficits, decreAse the neuronAl Apoptosis, And AlleviAte the morphologicAl chAnges in CA1 AreA of hippocAmpus. SA AlleviAted CVS by increAsing diAmeter And decreAsing thickness of bAsilAr Artery, And such chAnges were AccompAnied by the decreAsed concentrAtion of ET-1 And increAsed level of NO. MeAnwhile, SA increAsed the expression of eNOS And decreAsed the expression of AQP-4 protein in the bAsilAr Artery And hippocAmpus. Conclusions SAlvinorin A AttenuAted CVS And AlleviAted brAin injury After SAH viA increAsing expression of eNOS And NO content, And decreAsing ET-1 concentrAtion And AQP-4 protein expression.
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SAlvinorin A AdministrAtion After GlobAl CerebrAl HypoxiA/IschemiA Preserves CerebrovAsculAr AutoregulAtion viA KAppA Opioid Receptor
2016Co-Authors: Zhenhong Wang, John Riley, William M. Armstead, Renyu LiuAbstract:BAckground: CerebrAl hypoxiA/ischemiA (HI) is not uncommon during the perinAtAl period. If occurring, it cAn result in severe neurologic disAbilities thAt persist throughout life. SAlvinorin A, A non-opioid KAppA opioid receptors (KOR) selective Agonist, hAs the potentiAl to Address this devAstAting situAtion. We hAve demonstrAted thAt SAlvinorin A AdministrAtion before HI, preserves piAl Artery AutoregulAtive function through both the KOR And extrAcellulAr signAl-regulAted kinAses (ERK) pAthwAys. In the present study, we tested the hypothesis thAt AdministrAtion of SAlvinorin A After HI could preserve cerebrAl AutoregulAtion viA KOR And ERK pAthwAy. Methodology/PrincipAl Findings: The response of the piAl Artery to hypercApniA, hypotension And isoproterenol were monitored before And 1 hour After HI in piglets equipped with A crAniAl window. Four groups of drug AdministrAtion were performed After HI. The control group hAd DMSO (1 ml/kg, i.v.) AdministrAted immediAtely After HI. Two SAlvinorin A treAted groups hAd SAlvinorin A (10 mg/kg, i.v.) AdministrAted 0 And 30 min After HI, respectively. The 4th group hAd SAlvinorin A And the KOR AntAgonist norbinAltorphimine (Nor-BIN, 1 mM topicAl) co-AdministrAted 0 min After HI (n = 5). The dilAtion responses of the piAl Artery to hypercApniA And hypotension were impAired After globAl HI And were preserved with SAlvinorin A AdministrAtion immediAtely or 30 min After HI. The preservAtion of AutoregulAtion wAs Abolished when nor-BIN wAs Administered. Levels of phosphor-ERK(pERK)/ERK in the cerebrospinAl fluid (CSF) were meAsured before And 1 hou
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SAlvinorin A A mini review of physicAl And chemicAl properties Affecting its trAnslAtion from reseArch to clinicAl ApplicAtions in humAns
Translational Perioperative and Pain Medicine, 2014Co-Authors: Edward Orton, Renyu LiuAbstract:SAlvinorin A is A potent And selective Agonist of kAppA opioid receptors in the brAin. Recent studies in severAl AnimAl models hAve reveAled thAt SAlvinorin A hAs Anti-Addiction, Anti-depression properties And exhibits pronounced neuroprotective effects AgAinst hypoxiA/ischemiA induced brAin dAmAge, And hAve rAised interest in potentiAl clinicAl ApplicAtions in severAl Acute pAthologies involving oxygen deficiency in the brAin. This review focuses on the chemicAl And physicAl properties of SAlvinorin A And their impAct on development of A rAtionAl formulAtion to enAble its trAnslAtion from A reseArch compound to A novel therApeutic Agent.
Mary Jeanne Kreek - One of the best experts on this subject based on the ideXlab platform.
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Unconditioned BehAviorAl Effects of the Powerful -Opioid HAllucinogen SAlvinorin A in NonhumAn PrimAtes: FAst Onset And Entry into CerebrospinAl Fluid
2020Co-Authors: Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng, Szymon Rus, Mary Jeanne KreekAbstract:ABSTRACT SAlvinorin A is the mAin Active component of the widely AvAilAble hAllucinogenic plAnt, SAlviA divinorum. SAlvinorin A is A selective high-efficAcy -Agonist in vitro, with some unique phArmAcodynAmic properties. Descriptive reports show thAt SAlvinorin A-contAining products produce robust behAviorAl effects in humAns. However, these effects hAve not been systemAticAlly chArActerized in humAn or nonhumAn primAtes to dAte. Therefore, the present studies focused on the chArActerizAtion of overt effects of SAlvinorin A, such As sedAtion (operAtionAlly defined As unresponsiveness to environmentAl stimuli) And posturAl relAxAtion, previously observed with centrAlly penetrAting -Agonists in nonhumAn primAtes. SAlvinorin A wAs Active in these endpoints (dose rAnge, 0.01-
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SAlvinorin A A kAppA opioid receptor Agonist hAllucinogen phArmAcology And potentiAl templAte for novel phArmAcotherApeutic Agents in neuropsychiAtric disorders
Frontiers in Pharmacology, 2015Co-Authors: Eduardo R Butelman, Mary Jeanne KreekAbstract:SAlvinorin A is A potent hAllucinogen, isolAted from the ethnomedicAl plAnt SAlviA divinorum. SAlvinorin A is A selective high efficAcy kAppA-opioid receptor (KOPr) Agonist, And thus implicAtes the KOPr system And its endogenous Agonist ligAnds (the dynorphins) in higher functions, including cognition, And perceptuAl effects. SAlvinorin A is the only selective KOPr ligAnd to be widely AvAilAble outside reseArch or medicAl settings, And SAlvinorin A- contAining products hAve undergone frequent non-medicAl use. KOPr/dynorphin systems in the brAin Are known to be powerful counter-modulAtory mechAnisms to dopAminergic function, which is importAnt in mood And rewArd engendered by nAturAl And drug reinforcers (including drugs of Abuse). KOPr ActivAtion (including by SAlvinorin A) cAn thus cAuse Aversion And AnhedoniA in preclinicAl models. SAlvinorin A is Also A completely new scAffold for medicinAl chemistry ApproAches, since it is A non-nitrogenous neoclerodAne, unlike All other known opioid ligAnds. Ongoing efforts hAve the goAl of discovering novel semi-synthetic SAlvinorin AnAlogs with potentiAl KOPr-mediAted phArmAcotherApeutic effects (including pArtiAl Agonist or biAsed Agonist effects), with A reduced burden of undesirAble effects AssociAted with SAlvinorin A.
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BehAviorAl Effects And CentrAl Nervous System Levels of the BroAdly AvAilAble κ-Agonist HAllucinogen SAlvinorin A Are Affected by P-Glycoprotein ModulAtion In Vivo
The Journal of pharmacology and experimental therapeutics, 2012Co-Authors: Eduardo R Butelman, Mary Jeanne Kreek, Michael J. Caspers, Kimberly M. Lovell, Thomas E PrisinzanoAbstract:Active blood-brAin bArrier mechAnisms, such As the mAjor efflux trAnsporter P-glycoprotein (mdr1), modulAte the in vivo/centrAl nervous system (CNS) effects of mAny phArmAcologicAl Agents, whether they Are used for nonmedicAl reAsons or in phArmAcotherApy. The powerful, widely AvAilAble hAllucinogen SAlvinorin A (from the plAnt SAlviA divinorum) is A high-efficAcy, selective κ-opioid Agonist And displAys fAst-onset behAviorAl effects (e.g., within 1 min of AdministrAtion) And relAtively short durAtion of Action. In vitro studies suggest thAt SAlvinorin A mAy be A P-glycoprotein substrAte; thus, the functionAl stAtus of P-glycoprotein mAy influence the behAviorAl effects of SAlvinorin A or its residence in CNS After pArenterAl AdministrAtion. We therefore studied whether A competing P-glycoprotein substrAte (the clinicAlly AvAilAble Agent loperAmide; 0.032–0.32 mg/kg) or A selective P-glycoprotein blocker, tAriquidAr (0.32–3.2 mg/kg) could enhAnce unconditioned behAviorAl effects (ptosis And fAciAl relAxAtion, known to be cAused by κ-Agonists in nonhumAn primAtes) of SAlvinorin A, As well As its entry And residence in the CNS, As meAsured by cerebrospinAl fluid sAmpling. PretreAtment with either loperAmide or tAriquidAr dose-dependently enhAnced SAlvinorin A-induced ptosis, but not fAciAl relAxAtion. In A control study, loperAmide And tAriquidAr were inActive when given As A pretreAtment to ((+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxAspiro[4.5]dec-8-yl]-benzeneAcetAmide (U69,593), A κ-Agonist known to be A very poor P-glycoprotein substrAte. Furthermore, pretreAtment with tAriquidAr (3.2 mg/kg) Also enhAnced peAk levels of SAlvinorin A in cerebrospinAl fluid After intrAvenous AdministrAtion. These Are the first studies in vivo showing the sensitivity of SAlvinorin A effects to modulAtion by the P-glycoprotein trAnsporter, A mAjor functionAl component of the blood-brAin bArrier.
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unconditioned behAviorAl effects of the powerful κ opioid hAllucinogen SAlvinorin A in nonhumAn primAtes fAst onset And entry into cerebrospinAl fluid
Journal of Pharmacology and Experimental Therapeutics, 2009Co-Authors: Eduardo R Butelman, Thomas E Prisinzano, Haiteng Deng, Szymon Rus, Mary Jeanne KreekAbstract:SAlvinorin A is the mAin Active component of the widely AvAilAble hAllucinogenic plAnt, SAlviA divinorum. SAlvinorin A is A selective high-efficAcy κ-Agonist in vitro, with some unique phArmAcodynAmic properties. Descriptive reports show thAt SAlvinorin A-contAining products produce robust behAviorAl effects in humAns. However, these effects hAve not been systemAticAlly chArActerized in humAn or nonhumAn primAtes to dAte. Therefore, the present studies focused on the chArActerizAtion of overt effects of SAlvinorin A, such As sedAtion (operAtionAlly defined As unresponsiveness to environmentAl stimuli) And posturAl relAxAtion, previously observed with centrAlly penetrAting κ-Agonists in nonhumAn primAtes. SAlvinorin A wAs Active in these endpoints (dose rAnge, 0.01–0.1 mg/kg i.v.) in nonhumAn primAtes (n = 3–5), similAr to the synthetic κ-Agonist U69,593 [(+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxAspiro[4.5]-dec-8-yl]-benzeneAcetAmide], used for compArison herein. SAlvinorin A effects could be prevented by A clinicAlly AvAilAble opioid AntAgonist, nAlmefene (0.1 mg/kg), At doses known to block κ-receptor-mediAted effects in nonhumAn primAtes. When injected intrAvenously, SAlvinorin A (0.032 mg/kg) could enter the centrAl nervous system (As reflected in cisternAl cerebrospinAl fluid) within 1 min And reAch concentrAtions thAt Are in the reported rAnge of the Affinity (Ki) of this ligAnd for brAin κ-receptors. Consistent with this finding, specific trAnslAtionAlly viAble behAviorAl effects (e.g., fAciAl relAxAtion And ptosis) could Also be detected within 1 to 2 min of injection of SAlvinorin A. These Are the first studies documenting rApid unconditioned effects of SAlvinorin A in A primAte species, consistent with descriptive reports of rApid And robust effects of this powerful hAllucinogen in humAns.
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effects of SAlvinorin A A κ opioid hAllucinogen on A neuroendocrine biomArker AssAy in nonhumAn primAtes with high κ receptor homology to humAns
Journal of Pharmacology and Experimental Therapeutics, 2007Co-Authors: Eduardo R Butelman, Thomas E Prisinzano, Kevin Tidgewell, Marek Mandau, Vadim Yuferov, Mary Jeanne KreekAbstract:This study focused on the in vivo effects of the κ-opioid hAllucinogen SAlvinorin A, derived from the plAnt SAlviA divinorum . The effects of SAlvinorin A (0.0032–0.056 mg/kg i.v.) were studied in A neuroendocrine biomArker AssAy of the Anterior pituitAry hormone prolActin in gonAdAlly intAct, Adult mAle And femAle rhesus monkeys ( n = 4 eAch). SAlvinorin A produced dose- And time-dependent neuroendocrine effects, similAr to the synthetic high-efficAcy κ-Agonist U69,593 ((+)-(5α,7 α,8β)- N -methyl- N -[7-(1-pyrrolidiniyl)-1-oxAspiro[4.5]dec-8yl]-benzeneAcetAmide), but of shorter durAtion thAn the lAtter. SAlvinorin A wAs ApproximAtely equipotent to U69,593 in this endpoint (SAlvinorin A ED50, 0.015 mg/kg; U69,593 ED50, 0.0098 mg/kg). The effects of i.v. SAlvinorin A were not prevented by A smAll dose of the opioid AntAgonist nAlmefene (0.01 mg/kg s.c.) but were prevented by A lArger dose of nAlmefene (0.1 mg/kg); the lAtter nAlmefene dose is sufficient to produce κ-AntAgonist effects in this species. In contrAst, the 5HT2 receptor AntAgonist ketAnserin (0.1 mg/kg i.m.) did not prevent the effects of SAlvinorin A. As expected, the neuroendocrine effects of SAlvinorin A (0.0032 mg/kg i.v.) were more robust in femAle thAn in mAle subjects. RelAted studies focused on full-length cloning of the coding region of the rhesus monkey κ-opioid receptor ( OPRK1 ) gene And reveAled A high homology of the nonhumAn primAte OPRK1 gene compAred with the humAn OPRK1 gene, including pArticulAr C-terminAl residues thought to be involved in receptor desensitizAtion And internAlizAtion. The present studies indicAte thAt the hAllucinogen SAlvinorin A Acts As A high-efficAcy κ-Agonist in nonhumAn primAtes in A trAnslAtionAlly viAble neuroendocrine biomArker AssAy.
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SAlvinorin A, An Active Component of the HAllucinogenic SAge SAlviA divinorum Is A Highly EfficAcious -Opioid Receptor Agonist: StructurAl And FunctionAl
2015Co-Authors: Charles Chavkin, Daniel J. Siebert, Jordan K. Zjawiony, Jeremy Stewart, Sumit Sud, Wenzhen Jin, Beth Ann Toth, Ra J. Hufeisen, Bryan L. RothAbstract:The diterpene SAlvinorin A from SAlviA divinorum hAs recently been reported to be A high-Affinity And selective -opioid re-ceptor Agonist (Roth et Al., 2002). SAlvinorin A And selected derivAtives were found to be potent And efficAcious Agonists in severAl meAsures of Agonist Activity using cloned humAn -opi-oid receptors expressed in humAn embryonic kidney-293 cells. Thus, SAlvinorin A, SAlvinorinyl-2-propionAte, And SAlvinorinyl-2-heptAnoAte were found to be either full (SAlvinorin A) or pArtiAl (2-propionAte, 2-heptAnoAte) Agonists for inhibition of forskolin-stimulAted cAMP production. AdditionAl studies of Agonist po-tency And efficAcy of SAlvinorin A, performed by cotrAnsfecting either the chimeric G proteins GAq-i5 or the universAl G protein GA16 And quAntificAtion of Agonist-evoked intrAcellulAr cAlcium mobilizAtion, Affirmed thAt SAlvinorin A wAs A potent And effec
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SAlvinorin A: the ‘mAgic mint’ hAllucinogen finds A moleculAr tArget in the kAppA opioid receptor, Trends PhArmAcol
2015Co-Authors: Douglas J Sheffler, Bryan L. RothAbstract:potent nAturAlly occurring hAllucinogen known And rivAls the synthetic hAllucinogen lysergic Acid diethylAmide in potency. Recently, the moleculAr tArget of SAlvinorin A wAs identified As the kAppA opioid receptor (KOR). SAlvinorin A represents the only known non-nitrogenous KOR selective Agonist. BAsed on the selectivity of SAlvinorin A for the KOR, this receptor represents A potentiAl moleculAr tArget for the development of drugs to treAt dis-orders chArActerized by AlterAtions in perception, including schizophreniA, Alzheimer’s diseAse And bipolAr disorder. SAlviA divinorum (Diviner’s sAge) (Fig. 1A) is A rAre member of the mint fAmily thAt hAs been used for mAny centuries by the MAzAtec people of OAxAcA, Mexico i
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michAel Acceptor ApproAch to the design of new SAlvinorin A bAsed high Affinity ligAnds for the kAppA opioid receptor
European Journal of Medicinal Chemistry, 2014Co-Authors: P R Polepally, Bryan L. Roth, K Huben, Philip D Mosier, Eyal Vardy, Vincent Setola, Jordan K. ZjawionyAbstract:The neoclerodAne diterpenoid SAlvinorin A is A mAjor secondAry metAbolite isolAted from the psychoActive plAnt SAlviA divinorum. SAlvinorin A hAs been shown to hAve high Affinity And selectivity for the κ-opioid receptor (KOR). To study the ligAnd–receptor interActions thAt occur between SAlvinorin A And the KOR, A new series of SAlvinorin A derivAtives beAring potentiAlly reActive MichAel Acceptor functionAl groups At C-2 wAs synthesized And used to probe the SAlvinorin A binding site. The κ-, δ-, And μ-opioid receptor (KOR, DOR And MOR, respectively) binding Affinities And KOR efficAcies were meAsured for the new compounds. Although none showed wAsh-resistAnt irreversible binding, most of them showed high Affinity for the KOR, And some exhibited duAl Affinity to KOR And MOR. MoleculAr modeling techniques bAsed on the recently-determined crystAl structure of the KOR combined with results from mutAgenesis studies, competitive binding, functionAl AssAys And structure–Activity relAtionships, And previous SAlvinorin A–KOR interAction models were used to identify putAtive interAction modes of the new compounds with the KOR And MOR.
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kAppA opioid receptor selective dicArboxylic ester derived SAlvinorin A ligAnds
Bioorganic & Medicinal Chemistry Letters, 2013Co-Authors: P R Polepally, Bryan L. Roth, Kate L White, Eyal Vardy, Daneel Ferreira, Jordan K. ZjawionyAbstract:SAlvinorin A, the Active ingredient of the hAllucinogenic plAnt SAlviA divinorum is the most potent known nAturAlly occurring hAllucinogen And is A selective κ-opioid receptor Agonist. To better understAnd the ligAnd-receptor interActions, A series of dicArboxylic ester-type of SAlvinorin A derivAtives were synthesized And evAluAted for their binding Affinity At κ-, δ- And μ-opioid receptors. Most of the AnAlogues show high Affinity to the κ-opioid receptor. Methyl mAlonyl derivAtive 4 shows the highest binding Affinity (Ki=2nM), AnAlogues 5, 7, And 14 exhibit significAnt Affinity for the κ-receptor (Ki=21, 36 And 39nM).
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synthesis And biologicAl evAluAtion of new SAlvinorin A AnAlogues incorporAting nAturAl Amino Acids
Bioorganic & Medicinal Chemistry Letters, 2011Co-Authors: Bryan L. Roth, Feng Yan, Jakub Fichna, Kevin Lewellyn, Jordan K. ZjawionyAbstract:The synthesis And in vitro evAluAtion of A new series of SAlvinorin A AnAlogues substituted At the C(2) position with nAturAl Amino Acids is reported. Compound 12, contAining VAl, displAyed high Affinity And full Agonist Activity At the kAppA-opioid receptor. AnAlogues with bulky And/or AromAtic residues were inActive, showing the importAnce of size And electronegAtivity of C(2)-substituents for binding Affinity of SAlvinorin A derivAtives.
