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Background and Purpose: Opioid‐based drugs are the gold standard medicines for pain relief. However, tolerance and several side effects (i.e. constipation and dependence) may occur upon chronic opioid administration. Photopharmacology is a promising approach to improve the benefit/risk profiles of these drugs. Thus, opioids can be locally activated with high spatiotemporal resolution, potentially minimizing systemic‐mediated adverse effects. Here, we aimed at developing a morphine photo‐derivative (photocaged morphine), which can be activated upon light irradiation both in vitro and in vivo. Experimental Approach Light‐dependent activity of pc‐morphine was assessed in cell‐based assays (intracellular calcium accumulation and electrophysiology) and in mice (formalin animal model of pain). In addition, tolerance, constipation and dependence were investigated in vivo using experimental paradigms. Key results: In mice, pc‐morphine was able to elicit antinociceptive effects, both using external light‐irradiation (hind paw) and spinal cord implanted fibre‐optics. In addition, remote morphine photoactivation was devoid of common systemic opioid‐related undesired effects, namely, constipation, tolerance to the analgesic effects, rewarding effects and naloxone‐induced withdrawal. Conclusion and Implications: Light‐dependent opioid‐based drugs may allow effective analgesia without the occurrence of tolerance or the associated and severe opioid‐related undesired effects. LINKED ARTICLES: This article is part of a themed issue on Advances in Opioid Pharmacology at the Time of the Opioid Epidemic. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v180.7/issuetoc [ABSTRACT FROM AUTHOR]

Catecholamine‐triggered β‐adrenoceptor (β‐AR) signaling is essential for the correct functioning of the heart. Although both β1‐ and β2‐AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1‐AR have proven this receptor as the main target for the therapeutic effects of beta blockers in the heart. Here, we report a new strategy for the light‐control of β1‐AR activation by means of photoswitchable drugs with a high level of β1‐/β2‐AR selectivity. All reported molecules allow for an efficient real‐time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo‐2, can be reversibly photocontrolled. Strikingly, pAzo‐2 also enables a dynamic cardiac rhythm management on living zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target β1‐AR in native environments using light. [ABSTRACT FROM AUTHOR]

Photopharmacological tools enable the precise spatiotemporal control of small molecule drugs. Amongst them, caged compounds incorporate a photolabile moiety which is released under illumination, thus liberating the active molecule. Caging groups have long been known and many chemical scaffolds have already been used in different applications. However, most of the initial examples are cleaved with UV light, which suffers from low tissue permeability and cell damage. Recently, caging groups that are released under visible light have been reported, which expand their utility. In this review, we outline the chemical strategies that have been used to increase the absorption wavelengths; we compare their photophysical properties, discuss their synthetic accessibility, and exemplify some of their biological applications. [ABSTRACT FROM AUTHOR]

Type 4 metabotropic glutamate (mGluj) receptors are emerging targets for the treatment of various disorders. Accordingly, numerous mGluj-positive allosteric modulators (PAMs) have been identified, some of which also display agonist activity. To identify the structural bases for their allosteric action, we explored the relationship between the binding pockets of mGlu4 PAMs with different chemical scaffolds and their functional properties. By use of innovative mGlu4 biosensors and second-messenger assays, we show that all PAMs enhance agonist action on the receptor through different degrees of allosteric agonism and positive cooperativity. For example, whereas VU0155041 and VU0415374 display equivalent efficacies [log(τB) = 1.15 ± 0.38 and 1.25 ± 0.44, respectively], they increase the ability of L-AP4 to stabilize the active conformation of the receptor by 4 and 39 times, respectively. Modeling and docking studies identify 2 overlapping binding pockets as follows: a first site homologous to the pocket of natural agonists of class A GPCRs linked to allosteric agonism and a second one pointing toward a site topographically homologous to the Na+ binding pocket of class A GPCRs, occupied by PAMs exhibiting the strongest cooperativity. These results reveal that intrinsic efficacy and cooperativity of mGlu4 PAMs are correlated with their binding mode, and vice versa, integrating structural and functional knowledge from different GPCR classes. [ABSTRACT FROM AUTHOR]

The development of visual hallucinations (VH) is a frequent complication of Parkinson's disease (PD). Presence of hallucinations is one of the main risk factors associated with dementia, and severity progression of VH mainly contributes to impaired quality of life in PD. The neuropsychological features associated with severity progression of VH are unknown and might help to detect patients at risk of a more severe outcome. We aimed to explore the neuropsychological deficits associated with the different types of VH observed in PD, from minor hallucinations to well-formed VH with loss of insight. Prospective study of 57 PD patients with (n = 29) and without VH (n = 28) matched for age, education, antiparkinsonian medications, and disease duration. Description of VH was assessed by the Hallucinations and Psychosis item of the MDS-UPDRS. Cognition was assessed with the Parkinson's Disease-Cognitive Rating Scale (PD-CRS) and the Mattis Dementia Rating Scale (MDRS). Patients with minor VH did not differ from patients without VH in any cognitive domain. PD patients with major VH and insight retained performed worse on the action verbal fluency task ( P < 0.04), and patients with VH and loss of insight showed a greater impairment on the PD-CRS posterior cortical score ( P = 0.021) and the clock copying item ( P = 0.01). A double dissociation was found in the neuropsychological profile of patients with VH with and without loss of insight. While the presence of major VH with insight retained appeared related to a predominant frontal-striatal impairment, loss of insight was characterized by further impairment of cognitive functions related to posterior cortical areas. A comprehensible continuum pattern of clinical relationships emerged among VH and cognitive functioning in PD. © 2010 Movement Disorder Society. [ABSTRACT FROM AUTHOR]

The diagnosis of Parkinson's disease with dementia (PDD) is currently based on clinical criteria (DSM-IV, MDS-Task Force). In daily practice and research studies, these criteria still depend on the subjective impression of the examiner. Brief screening tests (BST) are helpful in identifying patients with PD with dementia, which can be difficult in patients with advanced PD. We aimed to develop a BST for PD, the PDD-Short Screen (PDD-SS), to accurately and quickly screen for PDD. In this prospective study, 70 patients with nondemented (age 73.8 ± 4.4) and 32 demented (age 73.8 ± 4.4) PD regularly attending a Movement Disorders Clinic were included. Diagnosis of dementia was based on DSM-IV criteria, CDR score ≥1, and PD-CRS total score ≤64. The PDD-SS, Mattis Dementia Rating Scale (MDRS), and Mini-Mental State Examination (MMSE) were administered to all participants. Validity, reliability, and discriminative power of the PDD-SS were examined. The final version of the scale included the items immediate and delayed verbal memory, clock drawing, alternating verbal fluency, and a questionnaire covering cognitive and psychiatric (hallucinations, apathy) symptoms common in PDD. A cutoff score ≤11 on the PDD-SS yielded high sensitivity (89.8%) and specificity (88.5%) for diagnosing PDD. The MDRS displayed similar accuracy, but the PDD-SS administration time was significantly shorter (4.8-6.9 vs. 17.5-25.2 minutes). Diagnosis of dementia using the PDD-SS was not influenced by age, education, or motor function. The PDD-SS appears as the first BST for diagnosing PDD, displays an excellent diagnostic accuracy, and takes 5 to 7 minutes to be administered. © 2010 Movement Disorder Society [ABSTRACT FROM AUTHOR]

The prevalence of dementia in Parkinson's disease (PD) is close to 30%, and its incidence is 4 to 6 times higher than in age-matched general population. PD with dementia (PDD) is mainly characterized by a predominant and progressive frontal-subcortical impairment. The Mattis Dementia Rating Scale (MDRS) is a commonly used screening test that sensitively measures the degree of frontal-subcortical defects. Although the MDRS has been validated as a screening test of cognitive dysfunction in nondemented PD patients (PD-ND), its utility for screening dementia in PD is unknown. In order to validate the MDRS for diagnosis of PDD it was prospectively administered to 92 PD patients (57 PD-ND, 35 PDD) fulfilling UK-PDSBB criteria. Dementia was diagnosed according to DSM-IV-TR and a Clinical Dementia Rating (CDR) scale score ≥1. Univariate, logistic regression, and ROC curve analysis were carried out to measure the discriminative power of MDRS in PDD. Regression analysis showed MDRS total scores to independently differentiate PD-ND from PDD ( P < 0.001). Age and education did not predict the presence of dementia. ROC curve analysis showed a cut-off score of ≤123 on the MDRS total scores to yield high sensitivity (92.65%), specificity (91.4%), positive and negative predictive values (PPV 83.3%, NPV 96.4%). A brief version of the MDRS obtained by the addition of the memory, initiation/perseveration, and conceptualization subscores yielded similar discriminant properties. The MDRS has an excellent discriminant ability to diagnose dementia in PD and provides an objective measure to distinguish PD-ND from PDD. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Cognitive defects associated with cortical pathology may be a marker of dementia in Parkinson's disease (PD). There is a need to improve the diagnostic criteria of PD dementia (PDD) and to clarify the cognitive impairment patterns associated with PD. Current neuropsychological batteries designed for PD are focused on fronto-subcortical deficits but are not sensitive for cortical dysfunction. We developed a new scale, the Parkinson's Disease-Cognitive Rating Scale (PD-CRS), that was designed to cover the full spectrum of cognitive defects associated with PD. We prospectively studied 92 PD patients [30 cognitively intact (CogInt), 30 mild cognitive impairment (MCI), 32 PDD] and 61 matched controls who completed the PD-CRS and neuropsychological tests assessing the cognitive domains included in the PD-CRS. Acceptability, construct validity, reliability, and the discriminative properties of the PD-CRS were examined. The PD-CRS included items assessing fronto-subcortical defects and items assessing cortical dysfunction. Construct validity, test-retest and inter-rater reliability of PD-CRS total scores showed an intraclass correlation coefficient >0.70. The PD-CRS showed an excellent test accuracy to diagnose PDD (sensitivity 94%, specificity 94%). The PD-CRS total scores and confrontation naming item scores-assessing 'cortical' dysfunction-independently differentiated PDD from non-demented PD. Alternating verbal fluency and delayed verbal memory independently differentiated the MCI group from both controls and CogInt. The PD-CRS appeared to be a reliable and valid PD-specific battery that accurately diagnosed PDD and detected subtle fronto-subcortical deficits. Performance on the PD-CRS showed that PDD is characterized by the addition of cortical dysfunction upon a predominant and progressive fronto-subcortical impairment. © 2008 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Delusional misidentification syndromes (DMS) are a group of neuropsychiatric disorders due to disturbances in familiarity. DMS in organic diseases have been related to deficits in executive, memory, and visuospatial function. DMS are frequently reported in dementia with Lewy bodies (DLB). The presence of DMS in Parkinson's disease with dementia (PDD), which shares similar clinical and neuropsychological features with DLB, has not been studied. We describe the frequency and clinical features of DMS in a cohort of PDD patients, and we compare the neuropsychological profile between PDD patients with and without DMS. Prospective study of 30 PDD patients recruited from an outpatient setting, who received a structured behavioral interview assessing DMS and hallucinations, and a neuropsychological battery assessing executive function, memory, language, and visuospatial abilities. DMS were found in 16.7% of PDD patients. All DMS subjects also exhibited hallucinations that were significantly more severe than in PDD without DMS. DMS were responsive to neuroleptic drugs. PDD subjects with DMS presented a different neuropsychological profile than PDD subjects without DMS, with more severe memory and language deficits, but similar levels of executive and visuospatial impairment. DMS is a neuropsychiatric feature associated with PDD. Greater impairment in language and memory in PDD with DMS suggests a prominent role of the temporal cortex in the genesis of DMS in PDD. © 2007 Movement Disorder Society [ABSTRACT FROM AUTHOR]

Impulse control disorders (ICD) related to reward-processing dysfunction have been reported in Parkinson's disease (PD). The relationship between clinical markers of limbic dysfunction with demographic variables and cognitive status of PD is incompletely known. Our objective was to further characterize the relationship between limbic and cognitive dysfunction in a representative sample of nondemented PD patients without antecedents of ICD, as assessed by a risk-taking test of decision-making and a comprehensive neuropsychological battery. Prospective, controlled study of 35 nondemented PD patients and 31 matched controls who received the Iowa gambling task (IGT), the Mattis Dementia Rating Scale (MDRS) and verbal fluencies for global cognitive function, the Stroop and digit span tests for executive function, and the Rey Auditory Verbal Learning Test for memory. Compared to controls, PD patients performed significantly worse on the IGT. No clear relationship with demographic variables including dopaminergic treatment and motor response to levodopa (stable or fluctuating) emerged. Performance on the IGT was not related to executive function. In contrast, an inverse relationship was found between the IGT and memory and global cognitive performance, with patients with the better MDRS and memory scores performing significantly worse on the IGT. Our results confirm subclinical dysfunction of the limbic system in nondemented PD patients. Although impaired decision-making appears unrelated to executive dysfunction, patients with the better cognitive status appears more prone to assume risky behaviors. [ABSTRACT FROM AUTHOR]

The potassium xanthate D609 is widely accepted as a selective inhibitor of PC-specific phospholipase C (PC-PLC). The tricyclo[5.2.1.02,6]decane skeleton present in D609 can lead to four diastereomeric paris, but the diastereoselectivity of PC-PLC inhibition has never been reported. In this article, the synthesis of racemic D609 diastereomers and that of other xanthates, as well as their inhibitory effect on PC-PLC is reported. All xanthates obtained were competitive inhibitors of PC-PLC from Bacillus cereus (PLC Bc). No significant differences were found in the activity of D609 diastereomers ( K i 13–17 μM), suggesting the absence of a diastereochemical control of the enzyme by xanthate inhibitors. This result was confirmed after obtaining other potassium xanthates differing from D609 in the aliphatic chain. Among them, the potassium O-n-decenylxanthate was the most active inhibitor of PLC Bc ( K i 10 μM). These data indicate that the essential structural requirements for PLC Bc in vitro inhibition by xanthates are the presence of a Zn-chelating dithiocarbonate head and a sufficiently hydrophobic aliphatic moiety. [ABSTRACT FROM AUTHOR]

When fixed charges and enzyme molecules are not homogeneously distributed in a matrix, the degree of organization of charges, of enzyme molecules and of charges with respect to enzyme molecules modulate the enzyme reaction rate. The overall reaction velocity of the bound enzyme system may be expressed in terms of monovariate moments of the charge density distribution and of the bivariate moments of the charge and enzyme density distributions. With respect to the situation where fixed charges and enzyme molecules are randomly distributed in the matrix, the molecular organization, as expressed by the monovariate and bivariate moments results in an increase or a decrease, of the overall reaction rate, as well as in the appearance of a kinetic co-operativity. The degree of spatial organization of objects may be expressed quantitatively through the concept of minimal spanning tree. This concept may thus be applied to the quantification of the degree of order that may exist in the bidimensional distribution of enzyme molecules in a charged matrix. Primary walls of isolated plant cells in sterile culture behave as a polyanion and contain different enzymes. The spatial distribution in sycamore cell walls of an acid phosphatase has been studied through the concept of minimal spanning tree and shown to be non-randomly distributed in the polyanionic matrix, but clustered in that matrix. This spatial organization results in a modulation of the reaction rate of the cell-wall-bound phosphatase reaction. Both the theoretical and experimental results presented in this study leave little doubt as to the validity of the idea that in situ the organization of fixed charges and enzyme molecules modulate the overall dynamics of enzyme reactions. [ABSTRACT FROM AUTHOR]

The article presents the chemical structure for synthesis of sphingolipid analogues.