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Leeyuan Liuchen - One of the best experts on this subject based on the ideXlab platform.
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differentiAl regulAtion of the humAn κ opioid receptor by Agonists etorphine And levorphAnol reduced Dynorphin A And u50 488h induced internAlizAtion And phosphorylAtion
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Jianguo Li, Fengqin Zhang, Leeyuan LiuchenAbstract:We previously observed thAt ( trAns )-3,4-dichloro- N -methyl- N -[2-(1-pyrrolidinyl)-cyclohexyl]benzeneAcetAmide (U50,488H) promoted internAlizAtion And phosphorylAtion of the FLAG-tAgged humAn κ opioid receptor (FLAG-hkor) stAbly expressed in Chinese hAmster ovAry (CHO) cells. In this study, we compAred regulAtion of the FLAG-hkor expressed in CHO cells by U50,488H, Dynorphin A, etorphine, And levorphAnol, which were potent full Agonists As determined by stimulAtion of guAnosine 5′- O -(3-[ 35 S]thio)triphosphAte binding. Using fluorescence flow cytometry, we found thAt Dynorphin A(1-17), like U50,488H, promoted internAlizAtion of the FLAG-hkor in A time- And dose-dependent mAnner. The AntAgonists nAloxone And norbinAltorphimine, hAving no effect on FLAG-hkor internAlizAtion, effectively blocked Dynorphin A(1-17)- And U50,488H-induced internAlizAtion. Interestingly, the full Agonists etorphine And levorphAnol did not cAuse internAlizAtion of the FLAG-hkor but significAntly reduced Dynorphin A(1-17)- And U50,488H-induced internAlizAtion in A dose-dependent mAnner. Immunofluorescence stAining of FLAG-hkor yielded similAr results. Dynorphin A(1-17) And U50,488H enhAnced phosphorylAtion of FLAG-hkor to A greAter extent thAn etorphine, but levorphAnol did not increAse FLAG-hkor phosphorylAtion. Etorphine or levorphAnol decreAsed Dynorphin- or U50,488H-induced phosphorylAtion. It is likely thAt conformAtions of the hkor required for phosphorylAtion And initiAtion of internAlizAtion Are different from those for ActivAtion of G proteins. We Also exAmined whether the four Agonists hAd differentiAl effects on superActivAtion of AdenylAte cyclAse. PretreAtment with U50,488H, Dynorphin A(1-17), or etorphine enhAnced forskolin-stimulAted AdenylAte cyclAse Activity to ∼200 to 250% of the control, whereAs levorphAnol pretreAtment did not result in significAnt AdenylAte cyclAse superActivAtion. Thus, the degree of superActivAtion cAused by An Agonist is unrelAted to its Ability to promote internAlizAtion of the hkor.
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differentiAl regulAtion of the humAn κ opioid receptor by Agonists etorphine And levorphAnol reduced Dynorphin A And u50 488h induced internAlizAtion And phosphorylAtion
Journal of Pharmacology and Experimental Therapeutics, 2003Co-Authors: Fengqin Zhang, Xilu Jin, Leeyuan LiuchenAbstract:We previously observed thAt (trAns)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneAcetAmide (U50,488H) promoted internAlizAtion And phosphorylAtion of the FLAG-tAgged humAn kAppA opioid receptor (FLAG-hkor) stAbly expressed in Chinese hAmster ovAry (CHO) cells. In this study, we compAred regulAtion of the FLAG-hkor expressed in CHO cells by U50,488H, Dynorphin A, etorphine, And levorphAnol, which were potent full Agonists As determined by stimulAtion of guAnosine 5'-O-(3-[(35)S]thio)triphosphAte binding. Using fluorescence flow cytometry, we found thAt Dynorphin A(1-17), like U50,488H, promoted internAlizAtion of the FLAG-hkor in A time- And dose-dependent mAnner. The AntAgonists nAloxone And norbinAltorphimine, hAving no effect on FLAG-hkor internAlizAtion, effectively blocked Dynorphin A(1-17)- And U50,488H-induced internAlizAtion. Interestingly, the full Agonists etorphine And levorphAnol did not cAuse internAlizAtion of the FLAG-hkor but significAntly reduced Dynorphin A(1-17)- And U50,488H-induced internAlizAtion in A dose-dependent mAnner. Immunofluorescence stAining of FLAG-hkor yielded similAr results. Dynorphin A(1-17) And U50,488H enhAnced phosphorylAtion of FLAG-hkor to A greAter extent thAn etorphine, but levorphAnol did not increAse FLAG-hkor phosphorylAtion. Etorphine or levorphAnol decreAsed Dynorphin- or U50,488H-induced phosphorylAtion. It is likely thAt conformAtions of the hkor required for phosphorylAtion And initiAtion of internAlizAtion Are different from those for ActivAtion of G proteins. We Also exAmined whether the four Agonists hAd differentiAl effects on superActivAtion of AdenylAte cyclAse. PretreAtment with U50,488H, Dynorphin A(1-17), or etorphine enhAnced forskolin-stimulAted AdenylAte cyclAse Activity to ApproximAtely 200 to 250% of the control, whereAs levorphAnol pretreAtment did not result in significAnt AdenylAte cyclAse superActivAtion. Thus, the degree of superActivAtion cAused by An Agonist is unrelAted to its Ability to promote internAlizAtion of the hkor.
Victor J. Hruby - One of the best experts on this subject based on the ideXlab platform.
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cyclic non opioid Dynorphin A AnAlogues for the brAdykinin receptors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Alexander Kuzmin, Victor J. HrubyAbstract:AbstrAct Nerve injury And inflAmmAtion cAuse up-regulAtion of An endogenous opioid ligAnd, Dynorphin A (Dyn A), in the spinAl cord resulting in hyperAlgesiA viA the interAction with brAdykinin receptors (BRs). This is A non-opioid neuroexcitAtory effect thAt cAnnot be blocked by opioid AntAgonists. Our systemAtic structure–Activity relAtionships study on Dyn A identified leAd ligAnds 1 And 4 , Along with the key structurAl feAture (i.e. AmphipAthicity) for the BRs. However, the ligAnds showed very low metAbolic stAbility in plAsmA ( t 1/2 4 Afforded A cyclic Dyn A AnAlogue 5 thAt retAined the sAme rAnge of binding Affinity As the lineAr ligAnd with improved metAbolic stAbility ( t 1/2 >5 h) And therefore possesses the potentiAl As A phArmAcophoric scAffold to be utilized for drug development.
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vArious modificAtions of the AmphipAthic Dynorphin A phArmAcophore for rAt brAin brAdykinin receptors
Chemical Biology & Drug Design, 2016Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Robert Kupp, Michael Remesic, Cyf Ramoscolon, Sara M Hall, Christopher Chan, David Rankin, Victor J. HrubyAbstract:As A unique endogenous opioid ligAnd, Dynorphin A shows pArAdoxicAl neuroexcitAtory effects At brAdykinin receptors, And the effects Are known to be Amplified by the upregulAtion of Dynorphin A under chronic pAin And inflAmmAtory conditions. In our eArlier structure-Activity relAtionship studies, the AmphipAthic Dynorphin A frAgment, [Des-Arg(7) ]-Dyn A-(4-11), wAs identified As A phArmAcophore for the brAdykinin receptors Along with key structurAl feAtures. Here, further modificAtions of the phArmAcophore showed thAt the position of A Pro residue is Also An importAnt feAture becAuse of its role in mAking (or disrupting) A β-turn or 310 helix structure which is cruciAl for receptor recognition.
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Dynorphin A AnAlogs for the treAtment of chronic neuropAthic pAin
Future Medicinal Chemistry, 2016Co-Authors: Sara M Hall, Yeon Sun Lee, Victor J. HrubyAbstract:Chronic pAin is one of the most ubiquitous diseAses in the world, but treAtment is difficult with conventionAl methods, due to undesirAble side effects of treAtments And unknown mechAnisms of pAthologicAl pAin stAtes. The endogenous peptide, Dynorphin A hAs long been estAblished As A tArget for the treAtment of pAin. Interestingly, this unique peptide hAs both inhibitory (opioid in nAture) And excitAtory Activities (nonopioid) in the CNS. Both of these effects hAve been found to plAy A role in pAin And much work hAs been done to develop therApeutics to enhAnce the inhibitory effects. Here we will review the Dynorphin A compounds thAt hAve been designed for the modulAtion of pAin And will discuss where the field stAnds todAy.
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modificAtion of AmphipAthic non opioid Dynorphin A AnAlogues for rAt brAin brAdykinin receptors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Lindsay Lebaron, Ann Nguyen, Victor J. HrubyAbstract:AbstrAct It hAs been shown thAt under chronic pAin or nerve injury conditions, up-regulAted Dynorphin A (Dyn A) interActs with brAdykinin receptors (BRs) to cAuse hyperAlgesiA in the spinAl cord. Thus BRs AntAgonist cAn modulAte hyperAlgesiA by blocking Dyn A’s interAction with the BRs in the centrAl nervous system. In our eArlier structure–Activity relAtionship (SAR) study, [des-Arg 7 ]-Dyn A-(4–11) 13 wAs discovered As A minimum phArmAcophore for rAt brAin BRs with its AntAgonist Activity (Anti-hyperAlgesic effect) in in vivo tests using nAive or injured AnimAls. We hAve pursued further modificAtion on the [des-Arg 7 ]-Dyn A AnAlogues And identified A key insight into the phArmAcophore of the rAt brAin BRs: AmphipAthicity.
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AmphipAthic non opioid Dynorphin A AnAlogs to inhibit neuroexcitAtory effects At centrAl brAdykinin receptors
The 24th American Peptide Symposium, 2015Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Todd W Vanderah, Alexander Kuzmin, Victor J. HrubyAbstract:Nerve injury And inflAmmAtion cAuse up-regulAtion of Dynorphin A (Dyn A, H-Tyr-Gly-Gly-PheLeu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH) in the spinAl cord, which results in hyperAlgesiA viA the interAction with brAdykinin receptors (BRs) [1]. This is A non-opioid neuroexcitAtory effect thAt cAnnot be blocked by An opioid AntAgonist, nAloxone. On the bAsis of the fAct, systemAtic structure-Activity relAtionship study on Dyn A wAs performed to develop BRs AntAgonists thAt cAn block the hyperAlgesiA. As A result, LYS1044, [des-Arg]-Dyn A-(4-11), wAs identified As A leAd ligAnd Along with key insights into structurAl feAtures for the BRs recognition (i.e. AmphipAthicity) [2-4]. IntrAthecAl AdministrAtion of the leAd ligAnd reversed thermAl hyperAlgesiA And mechAnicAl hypersensitivity in nerve injured AnimAls And inhibited non-opioid Dyn A-induced motor impAirment And hyperAlgesiA in nAive AnimAls. Yet, this ligAnd showed very low metAbolic stAbilities in plAsmA And wAs completely degrAded within 4 hours of incubAtion (hAlf-life < 1 hour). Therefore, in An effort to improve the metAbolic stAbility And Also to enhAnce the blood brAin bArrier permeAbility, vArious modificAtions were performed on Dyn A structure. Here we report design And synthesis of cyclic Dyn A AnAlogues And their biologicAl Activities.
Frank Porreca - One of the best experts on this subject based on the ideXlab platform.
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cyclic non opioid Dynorphin A AnAlogues for the brAdykinin receptors
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Alexander Kuzmin, Victor J. HrubyAbstract:AbstrAct Nerve injury And inflAmmAtion cAuse up-regulAtion of An endogenous opioid ligAnd, Dynorphin A (Dyn A), in the spinAl cord resulting in hyperAlgesiA viA the interAction with brAdykinin receptors (BRs). This is A non-opioid neuroexcitAtory effect thAt cAnnot be blocked by opioid AntAgonists. Our systemAtic structure–Activity relAtionships study on Dyn A identified leAd ligAnds 1 And 4 , Along with the key structurAl feAture (i.e. AmphipAthicity) for the BRs. However, the ligAnds showed very low metAbolic stAbility in plAsmA ( t 1/2 4 Afforded A cyclic Dyn A AnAlogue 5 thAt retAined the sAme rAnge of binding Affinity As the lineAr ligAnd with improved metAbolic stAbility ( t 1/2 >5 h) And therefore possesses the potentiAl As A phArmAcophoric scAffold to be utilized for drug development.
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vArious modificAtions of the AmphipAthic Dynorphin A phArmAcophore for rAt brAin brAdykinin receptors
Chemical Biology & Drug Design, 2016Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Robert Kupp, Michael Remesic, Cyf Ramoscolon, Sara M Hall, Christopher Chan, David Rankin, Victor J. HrubyAbstract:As A unique endogenous opioid ligAnd, Dynorphin A shows pArAdoxicAl neuroexcitAtory effects At brAdykinin receptors, And the effects Are known to be Amplified by the upregulAtion of Dynorphin A under chronic pAin And inflAmmAtory conditions. In our eArlier structure-Activity relAtionship studies, the AmphipAthic Dynorphin A frAgment, [Des-Arg(7) ]-Dyn A-(4-11), wAs identified As A phArmAcophore for the brAdykinin receptors Along with key structurAl feAtures. Here, further modificAtions of the phArmAcophore showed thAt the position of A Pro residue is Also An importAnt feAture becAuse of its role in mAking (or disrupting) A β-turn or 310 helix structure which is cruciAl for receptor recognition.
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modificAtion of AmphipAthic non opioid Dynorphin A AnAlogues for rAt brAin brAdykinin receptors
Bioorganic & Medicinal Chemistry Letters, 2015Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Lindsay Lebaron, Ann Nguyen, Victor J. HrubyAbstract:AbstrAct It hAs been shown thAt under chronic pAin or nerve injury conditions, up-regulAted Dynorphin A (Dyn A) interActs with brAdykinin receptors (BRs) to cAuse hyperAlgesiA in the spinAl cord. Thus BRs AntAgonist cAn modulAte hyperAlgesiA by blocking Dyn A’s interAction with the BRs in the centrAl nervous system. In our eArlier structure–Activity relAtionship (SAR) study, [des-Arg 7 ]-Dyn A-(4–11) 13 wAs discovered As A minimum phArmAcophore for rAt brAin BRs with its AntAgonist Activity (Anti-hyperAlgesic effect) in in vivo tests using nAive or injured AnimAls. We hAve pursued further modificAtion on the [des-Arg 7 ]-Dyn A AnAlogues And identified A key insight into the phArmAcophore of the rAt brAin BRs: AmphipAthicity.
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AmphipAthic non opioid Dynorphin A AnAlogs to inhibit neuroexcitAtory effects At centrAl brAdykinin receptors
The 24th American Peptide Symposium, 2015Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Michael Remesic, Cyf Ramoscolon, Sara M Hall, David Rankin, Todd W Vanderah, Alexander Kuzmin, Victor J. HrubyAbstract:Nerve injury And inflAmmAtion cAuse up-regulAtion of Dynorphin A (Dyn A, H-Tyr-Gly-Gly-PheLeu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp-Asn-Gln-OH) in the spinAl cord, which results in hyperAlgesiA viA the interAction with brAdykinin receptors (BRs) [1]. This is A non-opioid neuroexcitAtory effect thAt cAnnot be blocked by An opioid AntAgonist, nAloxone. On the bAsis of the fAct, systemAtic structure-Activity relAtionship study on Dyn A wAs performed to develop BRs AntAgonists thAt cAn block the hyperAlgesiA. As A result, LYS1044, [des-Arg]-Dyn A-(4-11), wAs identified As A leAd ligAnd Along with key insights into structurAl feAtures for the BRs recognition (i.e. AmphipAthicity) [2-4]. IntrAthecAl AdministrAtion of the leAd ligAnd reversed thermAl hyperAlgesiA And mechAnicAl hypersensitivity in nerve injured AnimAls And inhibited non-opioid Dyn A-induced motor impAirment And hyperAlgesiA in nAive AnimAls. Yet, this ligAnd showed very low metAbolic stAbilities in plAsmA And wAs completely degrAded within 4 hours of incubAtion (hAlf-life < 1 hour). Therefore, in An effort to improve the metAbolic stAbility And Also to enhAnce the blood brAin bArrier permeAbility, vArious modificAtions were performed on Dyn A structure. Here we report design And synthesis of cyclic Dyn A AnAlogues And their biologicAl Activities.
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structure Activity relAtionships of non opioid des Arg7 Dynorphin A AnAlogues for brAdykinin receptors
Bioorganic & Medicinal Chemistry Letters, 2014Co-Authors: Yeon Sun Lee, Frank Porreca, Josephine Lai, Robert Kupp, Cyf Ramoscolon, Sara M Hall, David Rankin, Jose Juan Ortiz, Victor J. HrubyAbstract:In our eArlier studies, brAdykinin receptors (BRs) were identified As A potentiAl tArget for the neuroexcitAtory effects of Dynorphin A (Dyn A) in the centrAl nervous system (CNS), And [des-Arg7]-Dyn A-(4–11) (6) wAs discovered As A leAd ligAnd to modulAte Dyn A-(2–13) induced neuroexcitAtory effects in the CNS As An AntAgonist. In An effort to gAin insights into key structurAl feAtures of the Dyn A for the BRs, we pursued further structure–Activity relAtionships (SAR) study on the [des-Arg7]-Dyn A AnAlogs And confirmed thAt All of the [des-Arg7]-Dyn A AnAlogues showed good binding Affinities At the BRs.
James H. Woods - One of the best experts on this subject based on the ideXlab platform.
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LocAl inhibitory effects of Dynorphin A-(1–17) on cApsAicin-induced thermAl AllodyniA in rhesus monkeys
European Journal of Pharmacology, 2000Co-Authors: K.j. Willmont, Andrew Burritt, Victor J. Hruby, James H. WoodsAbstract:Although Dynorphin A-(1–17) hAs been chArActerized in vitro As A high efficAcy κ-opioid receptor Agonist, functionAl studies of Dynorphin A-(1–17) following centrAl or systemic AdministrAtion indicAte the involvement of both opioid And non-opioid components. The Aim of this study wAs to investigAte whether locAl AdministrAtion of Dynorphin-relAted AnAlogs cAn AttenuAte cApsAicin (8-methyl-N-vAnillyl-6-nonenAmide)-induced nociception And whAt type of opioid receptor mediAtes the locAl Action of Dynorphin A-(1–17) in monkeys. CApsAicin (100 μg) wAs used to evoke A nociceptive response, thermAl AllodyniA, which wAs mAnifested As A reduced tAil-withdrAwAl lAtency in normAlly innocuous 46°C wArm wAter. Co-AdministrAtion of Dynorphin A-(1–17) (0.3–10 μg) with cApsAicin in the tAil dose-dependently inhibited thermAl AllodyniA; however, both non-opioid frAgments Dynorphin A-(2–17) (10–300 μg) And Dynorphin A-(2–13) (10–300 μg) were ineffective. LocAl AntiAllodyniA of Dynorphin A-(1–17) wAs AntAgonized by A smAll dose (100 μg) of An opioid receptor AntAgonist, quAdAzocine, Applied s.c. in the tAil. PretreAtment with A selective κ-opioid receptor AntAgonist, nor-binAltorphimine (nor-BNI), s.c. 320 μg in the tAil Also reversed locAl AntiAllodyniA of Dynorphin A-(1–17). Both locAlly effective doses of AntAgonists, when Applied s.c. in the bAck, did not AntAgonize locAl Dynorphin A-(1–17), indicAting thAt peripherAl κ-opioid receptors selectively mediAted the locAl Action of Dynorphin A-(1–17) in the tAil. In Addition, A much lArger dose of Dynorphin A-(1–17) (1000 μg), when Administered s.c. in the bAck or i.m. in the thigh, did not cAuse sedAtive or diuretic effects. These results suggest thAt in vivo opioid Actions of Dynorphin-relAted peptides cAn be differentiAted locAlly in this procedure. They Also indicAte thAt locAl ApplicAtion of peptidic ligAnds mAy be A useful medicAtion for locAlized pAin.
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LocAl inhibitory effects of Dynorphin A-(1-17) on cApsAicin-induced thermAl AllodyniA in rhesus monkeys.
European journal of pharmacology, 2000Co-Authors: K.j. Willmont, Andrew Burritt, Victor J. Hruby, James H. WoodsAbstract:Although Dynorphin A-(1-17) hAs been chArActerized in vitro As A high efficAcy kAppA-opioid receptor Agonist, functionAl studies of Dynorphin A-(1-17) following centrAl or systemic AdministrAtion indicAte the involvement of both opioid And non-opioid components. The Aim of this study wAs to investigAte whether locAl AdministrAtion of Dynorphin-relAted AnAlogs cAn AttenuAte cApsAicin (8-methyl-N-vAnillyl-6-nonenAmide)-induced nociception And whAt type of opioid receptor mediAtes the locAl Action of Dynorphin A-(1-17) in monkeys. CApsAicin (100 microg) wAs used to evoke A nociceptive response, thermAl AllodyniA, which wAs mAnifested As A reduced tAil-withdrAwAl lAtency in normAlly innocuous 46 degrees C wArm wAter. Co-AdministrAtion of Dynorphin A-(1-17) (0.3-10 microg) with cApsAicin in the tAil dose-dependently inhibited thermAl AllodyniA; however, both non-opioid frAgments Dynorphin A-(2-17) (10-300 microg) And Dynorphin A-(2-13) (10-300 microg) were ineffective. LocAl AntiAllodyniA of Dynorphin A-(1-17) wAs AntAgonized by A smAll dose (100 microg) of An opioid receptor AntAgonist, quAdAzocine, Applied s.c. in the tAil. PretreAtment with A selective kAppA-opioid receptor AntAgonist, nor-binAltorphimine (nor-BNI), s.c. 320 microg in the tAil Also reversed locAl AntiAllodyniA of Dynorphin A-(1-17). Both locAlly effective doses of AntAgonists, when Applied s.c. in the bAck, did not AntAgonize locAl Dynorphin A-(1-17), indicAting thAt peripherAl kAppA-opioid receptors selectively mediAted the locAl Action of Dynorphin A-(1-17) in the tAil. In Addition, A much lArger dose of Dynorphin A-(1-17) (1000 microg), when Administered s. c. in the bAck or i.m. in the thigh, did not cAuse sedAtive or diuretic effects. These results suggest thAt in vivo opioid Actions of Dynorphin-relAted peptides cAn be differentiAted locAlly in this procedure. They Also indicAte thAt locAl ApplicAtion of peptidic ligAnds mAy be A useful medicAtion for locAlized pAin.
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locAl inhibitory effects of Dynorphin A 1 17 on cApsAicin induced thermAl AllodyniA in rhesus monkeys
European Journal of Pharmacology, 2000Co-Authors: K.j. Willmont, Andrew Burritt, Victor J. Hruby, James H. WoodsAbstract:Although Dynorphin A-(1–17) hAs been chArActerized in vitro As A high efficAcy κ-opioid receptor Agonist, functionAl studies of Dynorphin A-(1–17) following centrAl or systemic AdministrAtion indicAte the involvement of both opioid And non-opioid components. The Aim of this study wAs to investigAte whether locAl AdministrAtion of Dynorphin-relAted AnAlogs cAn AttenuAte cApsAicin (8-methyl-N-vAnillyl-6-nonenAmide)-induced nociception And whAt type of opioid receptor mediAtes the locAl Action of Dynorphin A-(1–17) in monkeys. CApsAicin (100 μg) wAs used to evoke A nociceptive response, thermAl AllodyniA, which wAs mAnifested As A reduced tAil-withdrAwAl lAtency in normAlly innocuous 46°C wArm wAter. Co-AdministrAtion of Dynorphin A-(1–17) (0.3–10 μg) with cApsAicin in the tAil dose-dependently inhibited thermAl AllodyniA; however, both non-opioid frAgments Dynorphin A-(2–17) (10–300 μg) And Dynorphin A-(2–13) (10–300 μg) were ineffective. LocAl AntiAllodyniA of Dynorphin A-(1–17) wAs AntAgonized by A smAll dose (100 μg) of An opioid receptor AntAgonist, quAdAzocine, Applied s.c. in the tAil. PretreAtment with A selective κ-opioid receptor AntAgonist, nor-binAltorphimine (nor-BNI), s.c. 320 μg in the tAil Also reversed locAl AntiAllodyniA of Dynorphin A-(1–17). Both locAlly effective doses of AntAgonists, when Applied s.c. in the bAck, did not AntAgonize locAl Dynorphin A-(1–17), indicAting thAt peripherAl κ-opioid receptors selectively mediAted the locAl Action of Dynorphin A-(1–17) in the tAil. In Addition, A much lArger dose of Dynorphin A-(1–17) (1000 μg), when Administered s.c. in the bAck or i.m. in the thigh, did not cAuse sedAtive or diuretic effects. These results suggest thAt in vivo opioid Actions of Dynorphin-relAted peptides cAn be differentiAted locAlly in this procedure. They Also indicAte thAt locAl ApplicAtion of peptidic ligAnds mAy be A useful medicAtion for locAlized pAin.
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Agonist And AntAgonist effects of Dynorphin A-(1-13) in A thermAl Antinociception AssAy in rhesus monkeys.
The Journal of pharmacology and experimental therapeutics, 1995Co-Authors: Eduardo R. Butelman, James H. WoodsAbstract:The Agonist And AntAgonist effects of intrAvenously Administered Dynorphin A-(1-13) were chArActerized in the wArm wAter (50 And 55 degrees C) tAil withdrAwAl AssAy of Antinociception in rhesus monkeys. The peptide dose-dependently elevAted tAil withdrAwAl lAtencies in 50 degrees C wAter, but wAs ineffective in 55 degrees C wAter. The Antinociceptive effect of Dynorphin wAs surmountAbly AntAgonized by quAdAzocine (0.1 mg/kg) And nor-binAltorphimine (3.2 mg/kg), but wAs not AntAgonized by clocinnAmox (0.1 mg/kg); this pAttern of AntAgonism is consistent with A kAppA-opioid receptor mediAted effect. PretreAtment with Dynorphin A-(1-13) (0.032-3.2 mg/kg) AntAgonized the Antinociceptive effects of U50,488 And U69,593 in 55 degrees C wAter, suggesting A low efficAcy Action of the peptide At the receptors ActivAted by these kAppA Agonists. However, Dynorphin A-(1-13) (3.2 mg/kg) did not AntAgonize other kAppA Agonists: bremAzocine (0.018-0.056 mg/kg) And enAdoline (0.0056-0.018 mg/kg). TAken together, these Dynorphin A-(1-13) findings support the notion of functionAl kAppA-opioid receptor subtypes, And it AppeArs thAt Dynorphin A-(1-13) hAs limited efficAcy At one of these sites. FinAlly, Dynorphin A-(1-13) (0.32 mg/kg) Also AntAgonized the Antinociceptive effects of the mu-Agonist etonitAzene (0.0018-0.01 mg/kg).
Jane V Aldrich - One of the best experts on this subject based on the ideXlab platform.
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design synthesis And phArmAcologicAl Activities of Dynorphin A AnAlogues cyclized by ring closing metAthesis
Journal of Medicinal Chemistry, 2009Co-Authors: Wei Jie Fang, Thomas F Murray, Yanjun Cui, Jane V AldrichAbstract:Dynorphin A (Dyn A) is An endogenous ligAnd for kAppA (κ) opioid receptors. To restrict the conformAtionAl mobility, we synthesized severAl cyclic Dyn A-(1-11)NH2 AnAlogs on solid phAse utilizing ring-closing metAthesis (RCM) between the side chAins of Allylglycine (AllGly) residues incorporAted in positions 2, 5 And/or 8. CyclizAtions between the side chAins of AllGly gAve reAsonAble yields (56–74%) of All of the desired cyclic peptides. Both the cis And trAns isomers were obtAined for All of the cyclic peptides, with the rAtio of cis to trAns isomers depending on the position And stereochemistry of the AllGly. Most of the cyclic Dyn A-(1-11)NH2 AnAlogs exAmined exhibit low nAnomolAr binding Affinity for κ opioid receptors (Ki = 0.84–11 nM). In two of the three cAses the configurAtion of the double bond hAs A significAnt influence on the opioid receptor Affinity And Agonist potency. All of the peptides inhibited Adenylyl cyclAse (AC) Activity in A concentrAtion-dependent mAnner with full or close to full Agonist Activity. These potent Dyn A AnAlogs Are the first ones cyclized by RCM.
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nα benzyltyr1 cyclo d Asp5 dAp8 Dynorphin A 1 11 nh2 cyclized in the Address domAin is A novel κ opioid receptor AntAgonist
Journal of Medicinal Chemistry, 2005Co-Authors: Kshitij A Patkar, Thomas F Murray, Xiuzhen Yan, Jane V AldrichAbstract:The cyclic Dynorphin A AnAlogue [Nα-benzylTyr1,cyclo(d-Asp5,DAp8)]Dynorphin A-(1−11)NH2 (DAp = 2,3-diAminopropionic Acid) exhibits nAnomolAr Affinity (30 nM) And high selectivity (Ki rAtio (κ/μ/δ) = 1/194/330) for κ-opioid receptors. This AnAlogue AntAgonizes Dynorphin A-(1−13)NH2 At κ-opioid receptors in the Adenylyl cyclAse AssAy (KB = 84 nM). This is the first Dynorphin A-bAsed AntAgonist with modificAtions in the C-terminAl “Address” domAin thAt Alter efficAcy And thus represents A novel selective κ-opioid receptor AntAgonist.
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identificAtion of Arodyn A novel AcetylAted Dynorphin A 1 11 AnAlogue As A kAppA opioid receptor AntAgonist
Journal of Medicinal Chemistry, 2002Co-Authors: Marco A Bennett, Thomas F Murray, Jane V AldrichAbstract:Arodyn (AromAtic Dynorphin) is A novel AnAlogue of the opioid peptide Dynorphin A with A nonbAsic N-terminus thAt exhibits nAnomolAr Affinity (K(i) = 10 nM) And remArkAble selectivity for kAppA opioid receptors (K(i) rAtio (kAppA/mu/deltA) = 1/174/583). Arodyn completely reverses the Agonism of Dynorphin A (1-13)NH(2) in A concentrAtion-dependent mAnner in the Adenylyl cyclAse AssAy. Thus Arodyn is A novel kAppA opioid receptor selective AntAgonist thAt will be useful to study these receptors.
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Dynorphin A AnAlogs contAining A conformAtionAlly constrAined phenylAlAnine derivAtive in position 4 reversAl of preferred stereochemistry for opioid receptor Affinity And discriminAtion of kAppA vs deltA receptors
Chirality, 2001Co-Authors: Jane V Aldrich, Qi Zheng, Thomas F MurrayAbstract:AnAlogs of the opioid peptide [D-AlA8]Dynorphin A-(1-11)NH2 contAining opticAlly pure (R)- And (S)-2-AminotetrAlin-2-cArboxylic Acid (Atc) in position 4 were synthesized And evAluAted for opioid receptor Affinity. These peptides Are the first reported Dynorphin A AnAlogs contAining A conformAtionAlly constrAined Amino Acid in plAce of the importAnt AromAtic residue Phe4. By incorporAting resolved Atc isomers, the opioid receptor Affinity And the stereochemistry of the constrAined residue could be unAmbiguously correlAted. Both Dyn A AnAlogs contAining Atc in position 4 retAined nAnomolAr Affinity for κ And μ opioid receptors. Unexpectedly the peptide contAining (R)-Atc, corresponding to A conformAtionAlly constrAined D-Phe AnAlog, displAying higher Affinity for both κ And μ receptors thAn the peptide contAining (S)-Atc. In contrAst [D-Phe4,D-AlA8]Dyn A-(1-11)NH2 exhibited significAntly lower Affinity for κ And μ receptors thAn the pArent peptide, As expected. ConformAtionAl restriction of the Phe4 sidechAin or incorporAtion of D-Phe in position 4 hAd the lArgest effect on δ receptor Affinity, yielding compounds with negligible Affinity for these receptors. Thus, there AppeAr to be distinctly different structurAl requirements for this residue for κ vs. δ receptors, And it is possible to completely distinguish between these two receptors by chAnging A single residue in Dyn A. ChirAlity 13:125–129, 2001. © 2001 Wiley-Liss, Inc.
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Synthesis And opioid Activity of [D-Pro10]Dynorphin A-(1-11) AnAlogues with N-terminAl Alkyl substitution.
Journal of medicinal chemistry, 1997Co-Authors: Heekyung Choi, Thomas F Murray, Gary E. Delander, William K. Schmidt, Jane V AldrichAbstract:SeverAl N-terminAl di- And monoAlkylAted derivAtives of [d-Pro10]Dynorphin A-(1−11) were synthesized in order to explore the structure−Activity relAtionships for AntAgonist vs Agonist Activity At κ-opioid receptors. N,N-DiAlkylAted And N-monoAlkylAted (Alkyl = Allyl, benzyl, And cyclopropylmethyl (CPM)) tyrosine derivAtives were prepAred from tyrosine tert-butyl ester And the corresponding Alkyl hAlides. [d-Pro10]Dyn A-(2−11) wAs prepAred by solid phAse synthesis using Fmoc-protected Amino Acids, And the tyrosine derivAtives were coupled to the peptide with BOP ((benzotriAzol-1-yloxy)tris(dimethylAmino)phosphonium hexAfluorophosphAte). Both the degree of substitution And the identity of the Alkyl group Affected κ-receptor Affinity, selectivity, And efficAcy. All of the N-monoAlkylAted derivAtives exhibited much higher Affinity (Ki 200) compAred to the N,N-diAlkyl [d-Pro10]Dyn A-(1−11) AnAl...