ABSTRACT A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1 dopamine receptor antagonist SCH23390... more
ABSTRACT A series of 1-phenyl-, 4-phenyl-, and 1-benzyl-1,2,3,4-tetrahydroisoquinolines have been prepared as ring-contracted analogues of the prototypical D1 dopamine receptor antagonist SCH23390 [(R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H- 3-benzazepine]. The affinity and selectivity of these isoquinolines for D1 receptors was determined by three biochemical endpoints in membrane homogenates prepared from rat corpus striatum: the potency to complete for [3H]SCH23390 binding sites; the potency to compete for [3H]spiperone (a D2 receptor ligand) binding sites; and effects on dopamine-stimulated adenylate cyclase. Competitive binding measurements at D1 sites showed SCH23390 to possess the highest affinity, followed by 1-phenyl greater than 1-benzyl greater than 4-phenyl for the isoquinolines. These results were highly correlated with the ability of the test compounds to antagonize dopamine-stimulated adenylate cyclase (r = 0.98). None of the compounds alone stimulated cAMP formation at concentrations of 10 nM to 100 microM. D2 competition binding showed the 1-benzyl derivative to possess the highest affinity, followed by 4-phenyl greater than SCH23390 greater than 1-phenyl. The tertiary 1-phenyl derivative was more potent than the secondary 1-phenyl analogue in all assays. Interestingly, resolution and single-crystal X-ray analysis of the tertiary N-methyl-1-phenyltetrahydroisoquinoline showed the most active enantiomer to possess the S absolute configuration, in contrast to the benzazepine (R)-SCH23390.
Research Interests:
Research Interests:
Research Interests:
Research Interests:
ABSTRACT
Research Interests:
ABSTRACT
Research Interests:
Dinapsoline ((2); (±)-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline) is a full D1 dopamine agonist that also has significant D2 receptor affinity. Based on a similar pharmacophore, dinapsoline has pharmacological... more
Dinapsoline ((2); (±)-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline) is a full D1 dopamine agonist that also has significant D2 receptor affinity. Based on a similar pharmacophore, dinapsoline has pharmacological similarities to dihydrexidine ((1); (±)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine), the first high affinity full D1 agonist. Small alkyl substitutions on the dihydrexidine backbone are known to alter markedly the D1:D2 selectivity of dihydrexidine, and it was of interest to determine
Research Interests:
Research Interests:
BackgroundHigher nigral iron has been reported in Parkinson's disease (PD).ObjectiveThe aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment.MethodsSusceptibility magnetic... more
BackgroundHigher nigral iron has been reported in Parkinson's disease (PD).ObjectiveThe aim is to understand the dynamics of nigral iron accumulation in PD and its association with drug treatment.MethodsSusceptibility magnetic resonance imaging data were obtained from 79 controls and 18 drug‐naive (PDDN) and 87 drug‐treated (PDDT) PD patients. Regional brain iron in basal ganglia and cerebellar structures was estimated using quantitative susceptibility mapping. Nigral iron was compared between PDDN and PDDT subgroups defined by disease duration (early [PDE, <2 years], middle [PDM, 2–6 years], and later [PDL, >6 years]). Associations with both disease duration and types of antiparkinson drugs were explored using regression analysis.ResultsCompared to controls, PDDN had lower iron in the substantia nigra (P = 0.018), caudate nucleus (P = 0.038), and globus pallidus (P = 0.01) but not in the putamen or red nucleus. In contrast, PDDT had higher iron in the nigra (P < 0.001)...
Research Interests:
ImportanceThe specific pattern/trajectory of β-amyloid (Aβ) pathology spreading in Alzheimer’s disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood.ObjectiveTo determine if... more
ImportanceThe specific pattern/trajectory of β-amyloid (Aβ) pathology spreading in Alzheimer’s disease (AD), from default mode network (DMN) regions to sensory-motor areas, is well known, but poorly understood.ObjectiveTo determine if resting-state global brain activity is linked to early Aβ deposition in the DMN.DesignThis is a retrospect analysis of multi-modal and longitudinal data from the Alzheimer’s disease Neuroimaging Initiative (ADNI) cohort.SettingThe ADNI was a multicenter project involving 63 research centers.ParticipantsThe study included 144 participants (72.6 ± 7.5 years; 73 females) of whom 28 were controls, 21 had significant memory concerns, 72 had cognitive impairment (N=72), and 23 had AD. There were both baseline and 2-year follow-up data for Aβ-PET for 112 of the subjects. They were classified into following stages based on the CSF Aβ42 (CSF+: <192 ng/L) and cortical Aβ (PET+: >0.872 SUVR) levels: non-Aβ-accumulators (CSF-/PET-); early-Aβ-accumulators (CS...
Research Interests:
Research Interests:
Research Interests:
Research Interests: Medicine and Apomorphine
Research Interests:
Dopamine D1 agonists produce an ‘inverted‐U’ dose‐response on working memory‐related behavioral tasks (i.e., low doses improve but high doses have no effect or tend to impair performance). This dose‐dependency has been observed at the... more
Dopamine D1 agonists produce an ‘inverted‐U’ dose‐response on working memory‐related behavioral tasks (i.e., low doses improve but high doses have no effect or tend to impair performance). This dose‐dependency has been observed at the single neuron level in the prefrontal cortex, where the cellular basis of working memory is represented. Few studies, however, have examined this process at the neuron population level and its signaling mechanism(s) is still unclear. In the current study, two D1 agonists, 2‐methyldihydrexidine (2MDHX) and CY208,243 (CY208), were examined and compared in rats performing a spatial working memory‐related T‐maze task. 2MDHX is a full agonist at adenylate cyclase and a super‐agonist at β‐arrestin recruitment, whereas CY208 has relatively high intrinsic activity at adenylate cyclase, but much lower at β‐arrestin recruitment. Both compounds had inverted U‐dose response curves at both the behavioral and prefrontal neuron population level, albeit with distinct ...
Research Interests:
When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in... more
When the neuroleptic radioreceptor assay (NRRA) has been used to monitor total neuroleptic-like activity (NLA) in the blood of patients taking thioridazine, the NLA values obtained from the NRRA are much lower than values calculated in the same sample by measuring the actual concentrations of parent drug and active metabolites and multiplying these values by the relative potency of each compound. The present report demonstrates that in the NRRA for thioridazine or its active metabolites, the normal displacement of [3H]-spiperone from striatal membranes by thioridazine is altered in the presence of sera. The inclusion of serum (50 microliter/ml) distorts the sigmoidal displacement curves, such the resulting log-logit (or Hill) slope is markedly decreased. Similar serum-induced changes in the log-logit slope are seen for two active metabolites of thioridazine, but not for chlorpromazine or haloperidol. As a consequence, when one of these latter drugs is used as a standard, the NRRA su...
Research Interests: Pharmacology, Chemistry, Kinetics, Medicine, Biological Sciences, and 15 moreBiological Psychiatry, Humans, Female, Pubmed, Animals, Male, High Pressure Liquid Chromatography, Haloperidol, Cattle, Rats, Radioligand Assay, Chlorpromazine, Corpus striatum, Psychology and Cognitive Sciences, and Medical and Health Sciences
Although it is known that N-oxidation is a major route for the metabolism of tertiary amine drugs in humans, the extent to which N-oxide (NO) metabolites of clinically used phenothiazine antipsychotics contribute to the neuropharmacology... more
Although it is known that N-oxidation is a major route for the metabolism of tertiary amine drugs in humans, the extent to which N-oxide (NO) metabolites of clinically used phenothiazine antipsychotics contribute to the neuropharmacology of the parent drug has been uncertain. After direct lateral ventricular injection of rats, both fluphenazine-NO and trifluoperazine-NO (piperazinyl-4-NO) had significant antidopaminergic activity as shown by their antagonism of amphetamine-induced locomotion and, to a lesser extent, of apomorphine-induced stereotypy. In vitro, fluphenazine-NO and trifluoperazine-NO inhibited both [3H]spiperone binding to rat striatal membranes and dopamine-stimulated adenylate cyclase activity in striatal homogenates. Conversely, chlorpromazine (CPZ)-NO (side-chain oxide) did not have significant antidopaminergic activity in either in vitro test, nor did it block amphetamine or apomorphine-induced behavior when centrally administered. These latter results were surpr...
Research Interests:
Research Interests:
A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson’s disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging... more
A growing body of evidence suggests nigral iron accumulation plays an important role in the pathophysiology of Parkinson’s disease (PD), contributing to dopaminergic neuron loss in the substantia nigra pars compacta (SNc). Converging evidence suggests this accumulation might be related to, or increased by, serotonergic dysfunction, a common, often early feature of the disease. We investigated whether lower plasma serotonin in PD is associated with higher nigral iron. We obtained plasma samples from 97 PD patients and 89 controls and MRI scans from a sub-cohort (62 PD, 70 controls). We measured serotonin concentrations using ultra-high performance liquid chromatography and regional iron content using MRI-based quantitative susceptibility mapping. PD patients had lower plasma serotonin (p < 0.0001) and higher nigral iron content (SNc: p < 0.001) overall. Exclusively in PD, lower plasma serotonin was correlated with higher nigral iron (SNc: r(58) = − 0.501, p < 0.001). This c...
Research Interests:
We have investigated the interaction of the dopamine D1 receptor with ergoline‐based ligands to understand how non‐catechols activate this receptor. Here, we examined the roles of conserved aromatic residues (F6.51 and F6.52) in... more
We have investigated the interaction of the dopamine D1 receptor with ergoline‐based ligands to understand how non‐catechols activate this receptor. Here, we examined the roles of conserved aromatic residues (F6.51 and F6.52) in transmembrane six segment that are reported to be conserved sites for receptor activation. Mutations of F6.51 and F6.52 to alanine (F6.51A and F6.52A) dramatically decreased the binding affinity of ergolines. Consistent with the affinity data, the functional potency of these ligands at D1‐mediated cAMP synthesis was eliminated at the F6.51A receptor. Whereas F6.52A significantly reduced the potency of these ergolines (consistent with their decreased affinity), it did not decrease the maximal cAMP production. We also studied F6.51Y and F6.51W that were more likely to conserve aromatic/hydrophobic interactions of F6.51. Although F6.51Y did not restore the affinity decrease by F6.51A, it partially restored the potency and fully restored cAMP production. F6.51W ...
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
UK PubMed Central (UKPMC) is an archive of life sciences journal literature.
Research Interests: Chemistry, Drug interactions, Medicine, Dopamine, Cerebellum, and 15 morecyclic AMP, Pubmed, Animals, PARALYSIS, In Vivo, Cyclic nucleotide, Apomorphine, Nucleotide, cyclic GMP, Motor activity, Dopamine antagonists, dopaminergic, Corpus striatum, Antipsychotic agents, and Pharmacology and pharmaceutical sciences
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Research Interests:
Full dopamine D1 agonists have been shown to have excellent efficacy for Parkinson's disease (PD), equal to levodopa, the current gold standard therapy. Unfortunately, no full D1 agonist has been approved because all current full D1... more
Full dopamine D1 agonists have been shown to have excellent efficacy for Parkinson's disease (PD), equal to levodopa, the current gold standard therapy. Unfortunately, no full D1 agonist has been approved because all current full D1 agonists have poor oral bioavailability caused by a catechol group. We investigated the binding sites of non‐catechol D1 ligands using ergoline and tetrahydronaphthalene scaffold backbones to provide a structural basis for new drug design. Homology modeling suggests that several ergoline derivatives show a docking pose close to the conserved serines (S5.42, S5.43, and S5.46) in transmembrane 5 (TM5). Each of these serines was mutated to alanine (S5.42A, S5.43A, and S5.46A) to remove a potential hydrogen bonding site. As predicted, the S5.46A mutation significantly decreased the affinity of ergoline derivatives, and S5.43A mutation showed an equal or less decrease than S5.46 mutation. Conversely, the S5.42A mutation greatly increased the affinity of e...
Research Interests:
IntroductionWelding fumes contain a mixture of metals and are an epitype for environmental metal-related neurotoxicity. Past studies of welders focused largely on basal ganglia regions and their association with parkinsonism. This study... more
IntroductionWelding fumes contain a mixture of metals and are an epitype for environmental metal-related neurotoxicity. Past studies of welders focused largely on basal ganglia regions and their association with parkinsonism. This study evaluated medial temporal lobe (MTL) structures that play a key role in Alzheimer’s disease-like pathology.MethodsExposure history and whole blood metal levels were obtained from subjects with/without a history of welding (42 welders; 31 controls). MTL regions of interest (ROI) (hippocampus, entorhinal and parahippocampal cortices) were assessed by morphologic (volume and cortical thickness) and diffusion tensor imaging [mean (MD), axial (AD), radial diffusivity (RD) and fractional anisotropy (FA)] metrics. Cognition was evaluated using standard neuropsychological tests.ResultsWelders had higher blood levels of Cu, Fe, K, Mn, Pb, Se, and Zn (p’s<0.026) than controls. Welders had higher MD, AD, and RD in all MTL ROIs (p’s<0.040) and lower FA in ...
Research Interests:
Single-protein–based devices that integrate signal sensing with logical operations to generate functional outputs offer exceptional promise for monitoring and modulating biological systems. Engineering such intelligent nanoscale computing... more
Single-protein–based devices that integrate signal sensing with logical operations to generate functional outputs offer exceptional promise for monitoring and modulating biological systems. Engineering such intelligent nanoscale computing agents is challenging, as it requires the integration of sensor domains into a functional protein via intricate allosteric networks. We incorporate a rapamycin-sensitive sensor (uniRapR) and a blue light-responsive LOV2 domain into human Src kinase, creating a protein device that functions as a noncommutative combinatorial logic circuit. In our design, rapamycin activates Src kinase, causing protein localization to focal adhesions, whereas blue light exerts the reverse effect that inactivates Src translocation. Focal adhesion maturation induced by Src activation reduces cell migration dynamics and shifts cell orientation to align along collagen nanolane fibers. Using this protein device, we reversibly control cell orientation by applying the approp...
Research Interests:
Research Interests:
IntroductionMetal exposure has been associated with higher risk of neurodegenerative disorders such as Alzheimer’s disease (AD). We examined the potential link between welding-related metal co-exposure (e.g., Fe, Mn, Pb) and AD-related... more
IntroductionMetal exposure has been associated with higher risk of neurodegenerative disorders such as Alzheimer’s disease (AD). We examined the potential link between welding-related metal co-exposure (e.g., Fe, Mn, Pb) and AD-related structural and neurobehavioral metrics.MethodsSubjects with (welders; n=42) or without (controls; n=31) a history of welding were examined. Metal exposure was estimated by exposure questionnaires and whole blood metal levels. Brain metal accumulations were estimated by MRI R1 (Mn) and R2* (Fe) in the caudate, putamen, globus pallidus, red nucleus (RN), and hippocampus. AD-related structural differences were assessed by volume and diffusion tensor imaging metrics in the hippocampus, and neurobehavioral aspects by learning/memory task scores.ResultsCompared to controls, welders displayed higher blood metal levels (p’s <0.004) and R2* values in the caudate and RN (p’s<0.024). Caudate R2* values were associated with blood Fe (p=0.043), whereas RN R2...
Research Interests:
BackgroundCurrent pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately... more
BackgroundCurrent pharmacotherapy has limited efficacy and/or intolerable side effects in late-stage Parkinson’s disease (LsPD) patients whose daily life depends primarily on caregivers and palliative care. Clinical metrics inadequately gauge efficacy in LsPD patients.ObjectiveExplore if a D1/5 dopamine agonist will have efficacy in LsPD that will be detected most sensitively by caregivers in a phase I study.MethodsA double-blind controlled phase Ia/b study compared the D1/5 agonist PF-06412562 to levodopa/carbidopa in six LsPD patients. Throughout the study, caregivers were with the patients. Assessments included standard quantitative scales of motor function (MDS-UPDRS-III), alertness (Glasgow Coma and Stanford Sleepiness Scales), and cognition (Severe Impairment and Frontal Assessment Batteries) at baseline (Day 1) and thrice daily during drug testing (Days 2 and 3). Clinicians and caregivers completed clinical impression of change questionnaires, and caregivers participated in a...
Research Interests:
Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation... more
Lead is a nonessential metal and may be a coexposure in welding fumes. Preclinical data indicate lead may affect iron regulation. The current study investigated blood lead concentrations and their association with brain iron accumulation in workers with chronic welding fume exposure, with a focus on iron-rich subcortical regions of the cerebellum and basal ganglia. Occupational exposure, whole blood metal, and brain MRI data were obtained from 29 controls and 42 welders. R2* (1/T2*) and R1 (T1 relaxation rate) values were used to estimate brain iron and manganese content, respectively. Blood metals and brain R2* (in the red nucleus [RN], dentate nucleus, caudate, putamen, globus pallidus, and substantia nigra) were compared between groups. Associations between brain R2* values and exposure metrics were tested within each group, and analyses were adjusted for potential confounders. Welders had significantly higher levels of whole blood lead, manganese, iron, and copper. Welders also ...