Http Dx Doi Org 10 1080 0964704x 2012 678199, Jan 16, 2013
The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the an... more The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.
Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluoresce... more Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace [3H]SCH 23390 and [3H]spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis). The fluorescein derivatives of PPHT and SKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of the parent ligands. The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands. The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues. In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor. These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively. The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs wh... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which rais... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthet... more Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designat... more The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5 and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7 +/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine. Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast...
Http Dx Doi Org 10 1080 0964704x 2012 678199, Jan 16, 2013
The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the an... more The 1975 publication of Seeman et al. (Proc Nat Acad Sci, USA), reporting the discovery of the antipsychotic receptor in the brain, is a classic example of translational medicine research. In searching for a pathophysiological mechanism of psychosis, the team sought to identify sites that bound the antipsychotic drug haloperidol. Their criterion was that haloperidol bound to the site at one to two nanomoles per liter, corresponding to haloperidol concentrations found in spinal fluid or plasma water in treated patients. They requested de novo synthesis of tritiated haloperidol, and it readily detected specific haloperidol binding sites in brain striatum. With dopamine binding the haloperidol-labeled sites with higher potency than other neurotransmitters, the sites were named antipsychotic/dopamine receptors (now designated dopamine D2 receptors). Most significantly, they found that all antipsychotics bound these sites at concentrations and with a rank order of potencies that were directly related to the mean daily antipsychotic dose taken by patients with schizophrenia. Their findings enabled screening for new antipsychotics, initiated D2 receptor measurements in brain of living patients, and determination of minimum occupancy (65%) of D2 receptors for antipsychotic benefit. The collective work is generally viewed as providing a fundamental basis for the dopamine hypothesis of schizophrenia.
Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluoresce... more Fluorescent probes have been designed and developed for dopamine D-1 and D-2 receptors. Fluorescein and/or NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl) derivatives of PPHT (D-2 agonist), spiperone (D-2 antagonist), SKF 38393 (D-1 agonist), and SKF 83566 (D-1 antagonist) were synthesized via their amino-functionalized analogues and all ligands were pharmacologically evaluated by measuring their ability to displace [3H]SCH 23390 and [3H]spiperone from D-1 and D-2 receptor sites in caudate putamen of monkeys (Macaca fascicularis). The fluorescein derivatives of PPHT and SKF 83566 and the NBD derivatives of spiperone and SKF 83566 retained the high affinity and selectivity of the parent ligands. The NBD derivatives of PPHT showed higher D-2 receptor affinity and selectivity than their parent ligands. The enantiomers of the fluorescent derivatives of PPHT were also synthesized and were found to exhibit stereoselectivity in binding to the D-2 receptor, with the S enantiomers having a considerably higher affinity than their R analogues. In contrast to these results, the fluorescein derivative of SKF 38393 showed only a low affinity for the D-1 receptor. These fluorescein- and NBD-coupled D-1 and D-2 receptor ligands have considerable significance as potential probes in the study of distribution of the receptors at the cellular/subcellular level and of their mobility in membranes in normal/diseased states by use of fluorescence microscopic and fluorescence photobleaching recovery techniques, respectively. The development of these novel fluorescent probes should also provide new leads for the design and synthesis of additional fluorescent ligands with better fluorescent properties and/or higher affinity/selectivity for the DA receptors.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs wh... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which rais... more How do 'stimulants' reduce hyperactivity in children and adults? How can drugs which raise extracellular dopamine result in psychomotor slowing of hyperactive children when dopamine is known to enhance motor activity, such as in Parkinson's disease? These apparent paradoxes are the focus of this brief review on the mechanism of action of stimulant medications used in the treatment of children, and of an increasing number of adults who meet diagnostic criteria for attention deficit hyperactivity disorder.
Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthet... more Various transplanted leukemias and normal tissues of the mouse were tested for asparagine synthetase activity. Leukemias susceptible to suppression by asparaginase have little or no synthetase activity. In contrast, leukemias insensitive to asparaginase exhibit substantial and often very high asparagine synthetase activity. Asparaginase-resistant variants of sensitive leukemias also have considerable synthetase activity. Thus the requirement by certain malignant cells of exogenous asparagine, which entails sensitivity to asparaginase, may be ascribed to lack of asparagine synthetase. Development of asparaginase-resistant variants from asparaginase-sensitive lines is consistently associated with acquisition of asparagine synthetase activity.
Although cannabinoid effects on motor function have been extensively studied in rodents, the role... more Although cannabinoid effects on motor function have been extensively studied in rodents, the role of cannabinoids in regulating behavior in primates is relatively unknown. We compared the effects of cannabinoid agonists and dopamine antagonists on unconditioned behaviors in cynomolgus monkeys (Macaca fascicularis). We further investigated the therapeutic potential of cannabinoid antagonists in a primate model of Parkinson's disease. Drugs were administered i.m., and sessions were videotaped and rated by a "blind" observer using a rating scale. The dopamine antagonist haloperidol decreased locomotor activity and increased bradykinesia in three subjects. Haloperidol also produced a dose-dependent increase in freezing and catalepsy in two out of the three subjects. The cannabinoid agonist levonantradol dose-dependently decreased general and locomotor activity and increased bradykinesia. In contrast to haloperidol, levonantradol failed to produce freezing or catalepsy. At the dose range studied, tetrahydrocannabinol did not affect general or locomotor activity, but increased bradykinesia. In view of the psychomotor slowing induced by cannabinoid agonists, we investigated the therapeutic potential of the cannabinoid receptor antagonist SR141716A in an early and advanced stage of 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine-induced parkinsonism. In both models of Parkinson's disease, SR141716A failed to alleviate the motor deficits of parkinsonism. Cannabinoid agonists do not induce catalepsy in primates, a finding that differs from their effects in rodents. The primate may be more suitable than rodents for predicting the effects of cannabinoids and their therapeutic potential on select primate behaviors.
The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designat... more The potent cocaine analog 2 beta-carbomethoxy-3 beta-(4-fluorophenyl)-tropane (CFT, also designated WIN 35,428) was tritiated and evaluated as a molecular probe for cocaine receptors in caudate putamen membranes of cynomolgus monkeys. Kinetic, saturation, and competition experiments indicated that [3H]CFT, like [3H]cocaine, bound to at least two components. Association and dissociation of the radioligand at 0-4 degrees occurred in two phases; the t 1/2 for dissociation of the fast and slow components was 2.5 and 23 min, respectively. Saturation analysis revealed high and low affinity binding components with affinities (Kd) of 4.7 +/- 1.2 and 60 +/- 12 nM (means +/- SE) and densities (Bmax) of 50 +/- 18 and 290 +/- 20 pmol/g of tissue, respectively. [3H]CFT was displaced stereoselectively by the enantiomers of cocaine and by the diastereoisomers of the phenyltropane analog of cocaine. Most congeners displaced [3H]CFT fully, with shallow competition curves (nH, 0.69-0.81). In contrast...
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