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G-protein-coupled receptors (GPCRs) are a super-family of membrane proteins and major targets for drug development. However, many GPCRs drug candidates suffer from a lack of selectivity. Photopharmacology gives the possibility of modulating GPCR activity with an unprecedented local and temporal precision with the use of light. In this review, we compile and classify the different strategies in photopharmacology for GPCRs, we revise the different methods of analysis and characterization of light-regulated molecules used for GPCRs, and we give perspective of the impact of photopharmacology in research applications and in the development of new drugs.

2-(3,5-Dichlorophenylcarbamoyl)cyclohexanecarboxylic acid (1) is a potent and selective positive allosteric modulator of metabotropic glutamate receptor subtype 4 (mGluR4). The activity of 1 was reported to reside in the cis diastereomer with equal potency between its enantiomeric forms (Niswender et al., Mol. Pharmacol.2008, 74, 1345–1358). In the present study, the asymmetric synthesis of each of the cis enantiomers was performed, and their activities were compared with that of the racemic trans. In our assays, the cis enantiomers differ in potency, with one of them (1R,2S) higher and the other (1S,2R) lower than the racemic trans. High-level quantum chemical calculations were carried out to characterize the structures of minimum energy in all-isomer conformational space as well as particular intermediates between conformational transitions. Computational analysis identified structural features of 1 that can play a role in mGluR4 functionality and establish the basis for subsequent work, in which molecular chirality constructed on conformations derived from those found for the active (1R,2S) enantiomer can provide new ideas for drug discovery. Comparison between experimental and theoretical circular dichroism spectra confirmed both the absolute configuration of the (1R,2S) compound and its calculated most stable conformation, thereby supporting experimental and theoretical work., This study was supported in part by the Ministerio de Ciencia e Innovación (SAF2007-65913) and the Fundació La Marató de TV3 (Refs. 070530, 070531, and 07532). Computations were performed in part at the Centre de Supercomputació de Catalunya (CESCA).

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.

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 >or=1, and PD-CRS total score

A practical approach to the synthesis of phytosphingolipids containing the 1,2-diamino framework is described. The methodology relies on the regioselective ring-opening of phytosphingosine-derived N-nosylaziridines 4 and 6 with primary or secondary amines, acylation and subsequent deprotection steps. For practical purposes, N-substituted benzylamines were used as protected primary amine surrogates to avoid side-reactions in the course of the N-nosyl deprotection step.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A novel mechanism-based dihydroceramide desaturase inhibitor (XM462) in which the substrate C5 methylene group is replaced by a sulfur atom is reported. Dihydroceramide desaturase inhibition occurred both in vitro and in cultured cells with IC(50) values of 8.2 and 0.78 microM, respectively, at a substrate concentration of 10 microM. In vitro experiments showed that XM462 produced a mixed-type inhibition (K(i)=2 microM, alpha=0.83). LC-MS analyses showed that accumulation of endogenous dihydroceramides occurred in cells upon treatment with XM462 in serum-free medium, whereas ceramides built up in controls. In addition, XM462 was found to be metabolised to its 1-glucosyl and 1-phosphocholine derivatives, and to the products of N-deacylation and reacylation with palmitoyl and stearoyl groups. In Jurkat A3 cells cultured in serum-free medium, viability, as the percentage of trypan blue unstained cells in total cells, was reduced upon XM462 treatment (5 microM, 24 h), but not in controls. The interest of this compound is discussed.

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.

A simple solution-phase protocol for the synthesis of ceramide analogues from easily accessible enantiopure scaffolds is disclosed. The method relies on the use of nucleophilic thiolates or phenoxides and appropriate supported reagents or scavengers to give the target compounds in good overall yields. The method is easily adaptable to combinatorial protocols and also amenable to automated processes for the generation of small-to-medium-sized libraries for further screening.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

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.

Sphingolipids comprise an important group of biomolecules, some of which have been shown to play important roles in the regulation of many cell functions. From a structural standpoint, they all share a long 2-amino-1,3-diol chain, which can be either saturated (sphinganine), hydroxylated at C4 (phytosphingosine), or unsaturated at C4 (sphingosine) as in most mammalian cells. N-acylation of sphingosine leads to ceramide, a key intermediate in sphingolipid metabolism that can be enzymatically modified at the C1-OH position to other biologically important sphingolipids, such as sphingomyelin or glycosphingolipids. In addition, both ceramide and sphingosine can be phosphorylated at C1-OH to give ceramide-1-phosphate and sphingosine-1-phosphate, respectively. To better understand the biological and biophysical roles of sphingolipids, many efforts have been made to design synthetic analogues as chemical tools able to unravel their structure-activity relationships, and to alter their cellular levels. This last approach has been thoroughly studied by the development of specific inhibitors of some key enzymes that play an important role in biosynthesis or metabolism of these intriguing lipids. With the above premises in mind, the aim of this review is to collect, in a systematic way, the recent efforts described in the literature leading to the development of new chemical entities specifically designed to achieve the above goals.

3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) is consumed as the racemate but some metabolic steps are enantioselective. In addition, chiral properties are preserved during MDMA biotransformation. A quantitative analytical methodology using gas chromatography/mass spectrometry (GC/MS) to determine enantioselective disposition in the body of MDMA and its main metabolites including 3,4-methylenedioxyamphetamine (MDA), 4-hydroxy-3-methoxymethamphetamine (HMMA), and 4-hydroxy-3-methoxyamphetamine (HMA) was developed. Plasma and urine samples were collected from a male volunteer. The analysis of MDMA, MDA, and 4-hydroxy-3-methoxy metabolites by GC/MS required a two-step derivatization procedure. The first step consisted of derivatization of the amine with enantiomerically pure Mosher's reagent ((R)-MTPCl). Triethylamine was used as a base to neutralize hydrochloric acid formed during the reaction allowing quantitative derivatization, which resulted in a substantial improvement in the sensitivity of the method compared with other previously described techniques. Further treatment with ammonium hydroxide was required since both amine and hydroxyl groups underwent derivatization in the reaction. Ammonium hydroxide breaks bonds formed with hydroxyl groups without affecting amine derivatives. The second derivatization step using hexamethyldisilazane was needed for metabolites containing phenol residues. This derivatization method permitted the stereochemically specific study of MDMA and its main monohydroxylated metabolites by GC/MS. A detailed study of the chemical reactions involved in the derivatization steps was indispensable to develop a straightforward, sensitive, and reproducible method for the analysis of the parent drug compound and its metabolites.

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 (PLCBc). 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 PLCBc (K i 10 μM). These data indicate that the essential structural requirements for PLCBc in vitro inhibition by xanthates are the presence of a Zn-chelating dithiocarbonate head and a sufficiently hydrophobic aliphatic moiety.

A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, β-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds.

The reaction of vinyl bromides bearing distal olefin or acetylene functionalities with tetracarbonylnickel in the presence of alcohols and triethylamine results in the formation of exo-methylene cyclic esters in a regioselective process. High influence of the bulkiness of the alcohol is found.

A diastereoselective and mild cyclization−quenching process based on the treatment of nitrogen-tethered halodienes with stoichiometric Ni(COD)2 is described. The success of this methodology relies on the presence of a distal amino group capable of coordinating with the metal in the transient vinyl or alkylnickel species, thus controlling the diastereoselectivity of the cyclization step and preventing Ni−H β-elimination prior to the quenching. In general, better results are obtained in cyclizations taking place via a 5-exo-trig process, and a diversity of mono- and bicyclic nitrogenated systems are afforded in high yields by the proper choice of starting halodienes and quenching reagents. The presence of 2,2‘-bipyridine as a ligand results in an acceleration of the process, and in some cases, higher diastereoselectivities and/or supression of the Ni−H β-elimination are observed.

Alkynylalkoxycarbene metal complexes react readily with tetraalkoxyethylenes to give the corresponding [2 + 2] cycloadducts in high yields. From these adducts the title compounds were obtained by DMSO oxidation and final hydrolysis of the acetal groups.

The extension of the Ni(CO) 4 promoted carbonylative cycloaddition of acetylenes and allyl halides to the 5–8 membered 3-halocycloolefins leads efficiently to the formation of the corresponding 4–5 fused 2-cyclopentenones with high regio and stereoselectivities.

The reaction of 1-bromomethyl-1-cycloalkenes and acetylenes in the presence of tetracarbonylnickel affords moderate to good yields of spirocyclopentenones in a regio and stereoselective process.

The title carbonylative cycloaddition of five- to eight-member ring 3-halo- and 1-(halomethyl)cycloalkenes with different acetylenes was studied. From moderate to good yields of ring-fused and spiro cyclopentenone derivatives were obtained, especially in the reaction with acctylenes bearing electron-withdrawing substituents by propa selection of the reaction conditions to avoid the acetylene polyinsertion and/or other side reactions from the organonickel intamediates

The addition of different nucleophilic compounds (aliphatic and aromatic alcohols, thiols and phosphines) to alkynylalkoxycarbene complexes has been studied. The reaction with smaller nucleophiles proceeds readily and regioselectively at the β-carbene position. With more substituted nucleophiles the reaction rate slowed down considerably. Addition of a catalytic amount of DBU (1,8-di-azabicyclo[5.4.0]undec-7-ene]) speeded up the reaction and improved the E/Z ratio.

Stereoselective syn addition of allyl bromide to acetylenes catalysed by palladium (II) bromide results in the formation of 1-bromo-1,4-dienes which were further converted to cyclopentenones through a Ni(CO)4 promoted carbonylation-cyclization process. Four CC bonds are formed by this two step sequence, leading to 2,3-substituted 5-methoxycarbonylmethylcyclopentenones 1. Application of this procedure to 2-butyne affords cyclopentenone 1c, an immediate precursor of the antibiotic methylenomicyn B.

The [Ni(CO) 4 ]-mediated carbonylative cycloaddition of alkynes and allyl halides first reported by Chiusoli, has been reviewed, extended and optimized for application to cyclopentenone synthesis. An insight into the reaction mechanism is also given to explain the results obtained, in particular the regio- and stereo-chemistry of the process.

Reaction of different vinyl bromides ( 1a–3a ), bearing phenyl substituted alkenyloxyalkyl groups, with Ni(CO) 4 affords the corresponding substituted cyclic ethers 1b–3b in moderate to good yields and high diastereoselectivity. In the cyclization of 1a , the stereoselectivity of the process can be reversed by the use of additives, such as KOAc, TlOAc, Cs 2 CO 3 , and KOCOCF 3 .

An asymmetric approach to the Ni(CO) 4 induced alkyne-allyl halide cyclization-carbonylation process by the use of homochiral acetylenic sulfoxides to afford enantiopure [5+8] fused and spiro cyclopentenones is reported.

Different approaches to the asymmetric synthesis of cyclopentenones by means of the Ni(CO) 4 -promoted alkyne-allyl halide cyclization-carbonylation are reported. The use of acetylenic sulfoxides 1 has proved effective for the synthesis of acyclic, fused [5+8], and spiro [5+5], [5+7], and [5+8] cyclopentenones, whereas placement of the aryl sulfoxide on the allylic system failed to afford any cycloadduct. Homochiral fused [5+8], and spiro [5+7] and [5+8] cyclopentenones have been obtained by this methodology. Finally, a modest enantioselectivity was observed when different homochiral α-substituted carboxylates were used as ligands in our reaction system.

The nickel promoted tandem cyclization-quenching of tethered aminobromodienes has been extended to the synthesis of 2,3,4-trisubstituted pyrrolidines. By a judicious choice of substituents on the starting aminohalodiene, the diastereoselectivity of the process can be efficiently controlled. When a chiral auxiliary on the nitrogen atom is used, enantiomerically enriched pyrrolidines can be obtained after removal of the auxiliary.

The reaction of 2-haloethylidenecycloalkanes (ring size: 5, 6, 7, 8) with either methyl-2-butynoate or 2-butynyl methyl ether and Ni(CO)4 in methanol affords mainly two type of bicyclic compounds: 5-cycloalkenylidenecyclopent-2-enones and 5-(1-cycloalkenyl)cyclopent-2-enones. The origin for the diversion of the process towards elimination instead of alkoxycarbonylation is interpreted as the result of the mutual conformation of the two rings in the intermediates favouring either elimination through enol formation or syn β-elimination. In this last case, the terminating step can proceed in two different modes, namely, intraannularly or interannularly. While for the acetylenic ester, the product from interannular elimination is exclusive or predominant regardless of the ring size of the starting halide, for the 2-butynyl methyl ether, the product distribution is found to strongly depend on the nature of the allyl component. Thus, in this case, intraannular elimination is exclusively found in the reaction of the cyclopentylidene halide, while products from interannular elimination are produced in the reaction of the eight-member homologue. Mixtures of the two types of compound are formed from the cyclic 6 and 7 allyl halides.

A catalytic version of the intramolecular Ni-promoted tandem cyclization-cyanation process is described. Generally, the reaction leads to mixtures of cyclic and open chain adducts in moderate to good yields. The presence of external bidendate nitrogen ligands, although not essential for the reaction outcome, provides stability to the catalytic system.

A simple, efficient, and diastereoselective zinc-promoted allylation of aldehydes with enantiopure (SS)-3-chloro-2-(p-tolylsulfinyl)-1-propene [(SS)-1] under aqueous Barbier conditions is described. The observed diastereoselectivity can be explained via an acyclic antiperiplanar transition state model.

A comparative study on the allylation of aldehydes with enantiopure ( S S )-2-( p -tolylsulfonyl)-prop-2-en-1-ol ( S S )- 1a and the corresponding chloride ( S S )- 1b under two different reaction systems is reported. In general, better yields were obtained from chloride ( S S )- 1b , whereas higher diastereoinduction was observed from alcohol ( S S )- 1a . The sense of diastereoinduction is the same in both systems and the stereochemistry of the major diastereomer has been determined. Moreover, the configurational stability of the sulfoxide group on the resulting sulfinyl homoallylic alcohols 3 has been proven in each reaction system, which demonstrates the efficiency of the sulfoxide group as chiral auxiliary in these allylation processes. Finally, as an example of the synthetic potential of the resulting adducts, a total synthesis of natural enantioenriched ( S )-nicotine from sulfinylalcohol 3h is reported.

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.

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

A simple solution-phase protocol for the synthesis of ceramide analogues from easily accessible enantiopure scaffolds is disclosed. The method relies on the use of nucleophilic thiolates or phenoxides and appropriate supported reagents or scavengers to give the target compounds in good overall yields. The method is easily adaptable to combinatorial protocols and also amenable to automated processes for the generation of small-to-medium-sized libraries for further screening.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)

A straightforward approach for the synthesis of a new series of amino phosphates structurally related to sphingosine‐1‐phosphate is described. The commercial availability of the required starting building blocks, the reduced number of steps, and the ease of purification of the intermediate and final compounds make the approach amenable to combinatorial protocols.

A versatile method for the synthesis of carbamates from an ‘in-situ’ generated polymer-supported chloroformate resin is presented. BTC (bis-trichloromethyl carbonate) is used as phosgene equivalent to afford a supported chloroformate, which, by sequential ‘one-pot’ reaction with a variety of alcohols and amines, furnishes the corresponding carbamates in high yields and purities.