Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on c...Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.展开更多
Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from t...Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.展开更多
Phosphodiesterase(PDE)inhibitors can improve sperm motility in patients with asthenozoospermia.However,the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadv...Phosphodiesterase(PDE)inhibitors can improve sperm motility in patients with asthenozoospermia.However,the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadvantages of requiring a high concentration and destroying sperm integrity.We examined the PDE10A inhibitor PF-2545920 to compare its ability to promote sperm motility with that of pentoxifylline and sildenafil.After seminal plasma was discarded,several semen samples were subjected to four treatments(control,PF-2545920,pentoxifylline,and sildenafil)to evaluate their ability to affect motility,viability,and spontaneous acrosome reactions.Intracellular calcium and adenosine triphosphate(ATP),mitochondrial membrane potential,and penetration through viscous medium were assessed by flow cytometry,luciferase,and hyaluronic acid after treatment with PF-2545920.Statistical analyses were performed using the analysis of variance statistical test.PF-2545920 elevated the percentage of motile spermatozoa compared to the control,pentoxifylline,and sildenafil groups at 10μmol l^(-1)(P<0.01).It is less toxic to GC-2spd mouse spermatocytes cells and spermatozoa and causes fewer spontaneous acrosomal reactions(P<0.05).PF-2545920 also increased mitochondrial membrane potential(P<0.001)and altered intracellular calcium(P<0.05)in a dose-dependent manner,including increasing sperm hyaluronic acid penetrating ability(P<0.05).Therefore,PF-2545920 might be an excellent choiceforstimulatingthe spermmotility.展开更多
As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10A is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10A is primarily expressed in the medium...As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10A is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10A is primarily expressed in the medium spiny neurons of the striatum,it has been implicated in a variety of neurological disorders.Indeed,inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system(CNS)pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component.A PDE10A-targeted positron emission tomography(PET)radioligand would enable a better assessment of the pathophysiologic role of PDE10A,as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate,thus accelerating the development of effective PDE10A inhibitors.In this study,we designed and synthesized a novel ^(18)F-aryl PDE10A PET radioligand,codenamed[^(18)F]P10A-1910([^(18)F]9),in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination.[^(18)F]9 possessed good in vitro binding affinity(IC_(50)=2.1 nmol/L)and selectivity towards PDE10A.Further,[^(18)F]9 exhibited reasonable lipophilicity(logD=3.50)and brain permeability(P_(app)>10×10^(−6) cm/s in MDCK-MDR1 cells).PET imaging studies of[^(18)F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics.Preclinical studies in rodents revealed an improved plasma and brain stability of[^(18)F]9 when compared to the current reference standard for PDE10A-targeted PET,[^(18)F]MNI659.Further,dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of[^(18)F]9 for evaluating target occupancy in vivo in higher species.In conclusion,our results indicated that[^(18)F]9 is a promising PDE10A PET radioligand for clinical translation.展开更多
Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has sh...Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.展开更多
文摘Chronic exposure to drugs of abuse will give rise to persistent structural and functional changes in the central nervous system. These phenomena are usually referred as ′drug-induced neuroplasticity′ and depend on changes in gene expression. The cAMP response element binding protein(CREB),as a downstream molecule in mediating the actions of cAMP is an important transcriptional factor in establishing and maintaining addiction to drugs of abuse. Application of a PDE4 inhibitor attenuates the rewarding properties of cocaine and morphine. Given the fact that PDE10A is specifically located in striatum,an important structure involved in the reward circuit,we thus investigated the PDE10A inhibitormodulated the behavioral reinforcement exerted by morphine. The results show that MP-10 2.5 mg·kg^(-1),administered subcutaneously,significantly inhibited the acquisition of morphine-induced CPP. Moreover,MP-10 did not alter the expression of morphine-induced CPP,but did accelerate the extinction of morphine-induced CPP. Additionally,chronic treatment with MP-10 2.5 mg·kg^(-1)decreased expression of phosphorylated CREB(pC REB) in dorsomedial striatum,in shell of NAc,and in anterior cingulate cortex(ACC) as well as decreased expression of ΔFos B in the shell of NAc and ACC. These data indicate that PDE10A inhibition may have a potential therapeutic effect on addiction. Since the MP-10 has relative short metabolic Stability,we also developed a few novel potent new PDE10A selective inhibitor with improved stability and brain exposure. The new compound exhibited promising potential in schizophrenia and addiction treatment.
基金supported by the National Natural Science Foundation of China(Nos.21708052,21877134,81602955,and 81703341)Science Foundation of Guangzhou City(201904020023,China)+2 种基金Fundamental Research Funds for the Central Universities(Nos.19ykpy126 and 19ykpy123,China)China Postdoctoral Science Foundation(Nos.2019M663325 and 2019M663326)Guangdong Province Higher Vocational Colleges&Schools Pearl River Scholar Funded Scheme(2016,China)
文摘Optimization efforts were devoted to discover novel PDE10 A inhibitors in order to improve solubility and pharmacokinetics properties for a long-term therapy against pulmonary arterial hypertension(PAH)starting from the previously synthesized inhibitor A.As a result,a potent and highly selective PDE10 A inhibitor,14·3 HC1(half maximal inhibitory concentration,IC50=2.8 nmol/L and>3500-fold selectivity)exhibiting desirable solubility and metabolic stability with a remarkable bioavailability of50%was identified with the aid of efficient methods of binding free energy predictions.Animal PAH studies showed that the improvement offered by 14·3 HCl[2.5 mg/kg,oral administration(p.o.)]was comparable to tadalafil(5.0 mg/kg,p.o.),verifying the feasibility of PDE10 A inhibitors for the antiPAH treatment.The crystal structure of the PDE10 A-14 complex illustrates their binding pattern,which provided a guideline for rational design of highly selective PDE10 A inhibitors.
基金supported by the Shanghai Municipal Health Commission Young Foundation(No.20194Y0270)Science and Technology Commission of Shanghai Municipality(No.20ZR1448100).
文摘Phosphodiesterase(PDE)inhibitors can improve sperm motility in patients with asthenozoospermia.However,the most commonly reported nonselective PDE inhibitor pentoxifylline and PDE5 inhibitor sildenafil have the disadvantages of requiring a high concentration and destroying sperm integrity.We examined the PDE10A inhibitor PF-2545920 to compare its ability to promote sperm motility with that of pentoxifylline and sildenafil.After seminal plasma was discarded,several semen samples were subjected to four treatments(control,PF-2545920,pentoxifylline,and sildenafil)to evaluate their ability to affect motility,viability,and spontaneous acrosome reactions.Intracellular calcium and adenosine triphosphate(ATP),mitochondrial membrane potential,and penetration through viscous medium were assessed by flow cytometry,luciferase,and hyaluronic acid after treatment with PF-2545920.Statistical analyses were performed using the analysis of variance statistical test.PF-2545920 elevated the percentage of motile spermatozoa compared to the control,pentoxifylline,and sildenafil groups at 10μmol l^(-1)(P<0.01).It is less toxic to GC-2spd mouse spermatocytes cells and spermatozoa and causes fewer spontaneous acrosomal reactions(P<0.05).PF-2545920 also increased mitochondrial membrane potential(P<0.001)and altered intracellular calcium(P<0.05)in a dose-dependent manner,including increasing sperm hyaluronic acid penetrating ability(P<0.05).Therefore,PF-2545920 might be an excellent choiceforstimulatingthe spermmotility.
基金the support of K.C.Wong Education Foundation (China)financially supported by the National Natural Science Foundation of China (No.82071974)+3 种基金Shenzhen Basic Research Project (JCYJ20180503182116931, China)Guangdong Basic and Applied Basic Research Foundation (2020A1515011192, 2018A0303130052, China)Guangzhou Key Research Program on Brain Science (202007030008, China)the Fundamental Research Funds for the Central Universities (21619104, 21621051, China)
文摘As a member of cyclic nucleotide phosphodiesterase(PDE)enzyme family,PDE10A is in charge of the degradation of cyclic adenosine(cAMP)and guanosine monophosphates(cGMP).While PDE10A is primarily expressed in the medium spiny neurons of the striatum,it has been implicated in a variety of neurological disorders.Indeed,inhibition of PDE10A has proven to be of potential use for the treatment of central nervous system(CNS)pathologies caused by dysfunction of the basal ganglia–of which the striatum constitutes the largest component.A PDE10A-targeted positron emission tomography(PET)radioligand would enable a better assessment of the pathophysiologic role of PDE10A,as well as confirm the relationship between target occupancy and administrated dose of a given drug candidate,thus accelerating the development of effective PDE10A inhibitors.In this study,we designed and synthesized a novel ^(18)F-aryl PDE10A PET radioligand,codenamed[^(18)F]P10A-1910([^(18)F]9),in high radiochemical yield and molar activity via spirocyclic iodonium ylide-mediated radiofluorination.[^(18)F]9 possessed good in vitro binding affinity(IC_(50)=2.1 nmol/L)and selectivity towards PDE10A.Further,[^(18)F]9 exhibited reasonable lipophilicity(logD=3.50)and brain permeability(P_(app)>10×10^(−6) cm/s in MDCK-MDR1 cells).PET imaging studies of[^(18)F]9 revealed high striatal uptake and excellent in vivo specificity with reversible tracer kinetics.Preclinical studies in rodents revealed an improved plasma and brain stability of[^(18)F]9 when compared to the current reference standard for PDE10A-targeted PET,[^(18)F]MNI659.Further,dose–response experiments with a series of escalating doses of PDE10A inhibitor 1 in rhesus monkey brains confirmed the utility of[^(18)F]9 for evaluating target occupancy in vivo in higher species.In conclusion,our results indicated that[^(18)F]9 is a promising PDE10A PET radioligand for clinical translation.
基金supported by Aier Eye Hospital Group,Nos.AF2019001 and AF2019002(to SBT,KFS,YX and XSM)the National Natural Science Foundation of China,No.82074169(to XSM)+3 种基金Guangzhou Key Projects of Brain Science and Brain-Like Intelligence Technology of China,No.20200730009(to YX)Guangdong Grant Key Technologies for Treatment of Brain Disorders,China,No.2018B030332001(to YX)Natural Science Foundation of Guangdong Province of China,No.2021A1515012473(to XSM)Project of Administration of Traditional Chinese Medicine of Guangdong Province,No.20202045(to XSM)。
文摘Retinitis pigmentosa is a retinal disease characterized by photoreceptor degeneration.There is currently no effective treatment for retinitis pigmentosa.Although a mixture of lutein and other antioxidant agents has shown promising effects in protecting the retina from degeneration,the role of lutein alone remains unclear.In this study,we administered intragastric lutein to Pde6brd10 model mice,which display degeneration of retinal photoreceptors,on postnatal days 17(P17)to P25,when rod apoptosis reaches peak.Lutein at the optimal protective dose of 200 mg/kg promoted the survival of photoreceptors compared with vehicle control.Lutein increased rhodopsin expression in rod cells and opsin expression in cone cells,in line with an increased survival rate of photoreceptors.Functionally,lutein improved visual behavior,visual acuity,and retinal electroretinogram responses in Pde6brd10 mice.Mechanistically,lutein reduced the expression of glial fibrillary acidic protein in Müller glial cells.The results of this study confirm the ability of lutein to postpone photoreceptor degeneration by reducing reactive gliosis of Müller cells in the retina and exerting anti-inflammatory effects.This study was approved by the Laboratory Animal Ethics Committee of Jinan University(approval No.LACUC-20181217-02)on December 17,2018.
