RATIONALE: Second-generation antipsychotics demonstrate clinical efficacy with fewer extrapyramidal side effects compared with first-generation antipsychotics. One of the proposed explanations is the hypothesis of preferential extrastriatal dopamine D(2) receptor occupancy (limbic selectivity) by antipsychotics. In the present study, we focused on aripiprazole, which has a unique pharmacological profile with partial ...

Bivalent histamine H₂ receptor (H₂R) agonists were synthesized by connecting pharmacophoric 3-(2-amino-4-methylthiazol-5-yl)-, 3-(2-aminothiazol-5-yl)-, 3-(imidazol-4-yl)- or 3-(1,2,4-triazol-5-yl)-propylguanidine moieties by N^G-acylation with alkanedioic acids of various chain lengths. The compounds were investigated for H₂R agonism in GTPase and [³⁵S]GTPγS binding assays at guinea-pig (gp) and human (h) H₂R-GsαS fusion proteins including various ...

The structural and functional interaction between D(2) dopamine receptor (DR) and A(2A) adenosine receptor (AR) has suggested these two receptors as a pharmacological target in pathologies associated with dopamine dysfunction, such as Parkinson's disease. In transfected cell lines it has been demonstrated the activation of D(2)DR induces a significant negative ...

Maximakinin, a 19-residue peptide from the amphibian Bombina maxima, incorporates the full sequence of bradykinin (BK) at its C-terminus with a hydrophilic 10-residue N-terminal extension. As a putative venom component, it may stimulate BK B(2) receptors (B(2)Rs) in a distinct manner relative to the fragile mammalian agonist BK. Maximakinin affinity ...

Receptor internalization increases the flexibility and scope of GPCR signaling. CB(1) and CB(2) cannabinoid receptors undergo internalization following sustained exposure to agonists. However, it is not known if different agonists internalize CB(2) to different extents. Since CB(2) is a promising therapeutic target, understanding its trafficking in response to different agonists ...

Two novel highly sensitive colorimetric acetate anion receptors: 4-phenylazo-2-hydroxy-benzaldehyde 4-nitrophenylhydrazone (1) and 4-phenylazo-2-hydroxy-benzaldehyde 2,4-dinitrophenylhydrazone (2) based on azo derivative have been designed and synthesized. UV-vis experiments show that receptor 1 and receptor 2 can selectively recognize acetate in DMSO and even in 9/1 DMSO/H(2)O (v/v) mixtures. Meanwhile the color changes ...

The synthesis and binding properties of a tetrathiafulvalene (TTF)-calix[4]pyrrole receptor 2 appended with one 3,5-dinitrobenzoate guest moiety are reported. The preliminary studies revealed that the receptor is self-complexing into a dimer receptor 2•2. The self-complexation of the receptor leads to preorganization-in its 1,3-alternate conformation-and as a result hereof, the dimer ...

In this study we present the synthesis and some pharmacological properties of fourteen new analogues of neurohypophyseal hormones conformationally restricted in the N-terminal part of the molecule. All new peptides were substituted at position 2 with cis-1-amino-4-phenylcyclohexane-1-carboxylic acid (cis-Apc). Moreover, one of the new analogues: [cis-Apc(2), Val(4)]AVP was also prepared ...

Secretory phospholipase A(2) (sPLA(2)) isoforms are widely expressed in the brain and spinal cord. Group IIA sPLA(2) (sPLA(2)-IIA) has been shown to stimulate exocytosis and release of neurotransmitters in neuroendocrine PC12 cells and neurons, suggesting a role of the enzyme in neuronal signaling and synaptic transmission. However, the mechanisms by ...

The expression and physiology of purine receptors of the human blood-brain barrier endothelial cells were characterised by application of molecular biological, gene-silencing and Ca(2+)-imaging techniques to hCMEC/D3 cells. Reverse transcription polymerase chain reaction showed the expression of the G-protein-coupled receptors P2Y(2)-, P2Y(6)-, P2Y(11)- as well as the ionotropic P2X(4)-, P2X(5)- ...

A series of melatonin analogs obtained by the replacement of the ether methyl group with larger arylalkyl and aryloxyalkyl substituents was prepared in order to probe the melatonin receptors for MT(1) -selectivity. The most MT(1) -selective agents 11 and 15 were substituted with a Ph(CH(2) )(3) or a PhO(CH(2) )(3) ...

A petroleum ether extract of Kadsura longipedunculata enhanced the GABA-induced chloride current (I(GABA)) by 122.5±0.3% (n=2) when tested at 100μg/ml in Xenopuslaevis oocytes expressing GABA A receptors (α(1)β(2)γ(2S) subtype) in two-microelectrode voltage clamp measurements. Thirteen compounds were subsequently identified by HPLC-based activity profiling as responsible for GABA A receptor activity ...

Sensitization of the dopaminergic system has been proposed as a pathogenic mechanism of psychosis. It has been reported in sensitized animals that the proportion of high-affinity dopamine 2 (D(2)) receptors is increased, without changes in the total amount of D(2) receptors. This increase induces an exaggerated postsynaptic transmission of the ...

BACKGROUND AND PURPOSE  β(2) adrenoceptor agonists are important bronchodilators used for the treatment of chronic obstructive pulmonary disease and asthma. Clinical data on β(2) agonists show a range of onset and duration of action. We have investigated whether receptor binding kinetics of β(2) agonists influence the observed onset of action ...

The alpha-7 nicotinic acetylcholine receptor (α7nAChR) and the dopamine D(2) receptor (D(2) R) are both implicated in attentional processes and cognition, mediated in part through the prefrontal cortex (PFC). We examined the dual electron microscopic immunolabeling of α7nAChR and either D(2) R or the vesicular acetylcholine transporter (VAChT) in rodent ...

Background and Purpose.  Many cells express Proteinase Activated Receptor 2 (PAR(2) ) on their plasma membrane. PAR(2) is a sensor for proteolytic enzymes (e.g. trypsin, tryptase) which prune the receptor N-terminus, enabling it to signal via its transmembrane domain to intracellular G proteins that activate signaling networks. Studies on PAR(2) ...

A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC(50)) at the human Neuropeptide Y Y(2) receptor (NPY Y(2)). Six of the 23 analogs tested possessed an NPY Y(2) IC(50)⩽15nM. One member of this series, JNJ 31020028, is ...

Substance abuse and psychotic disorders have a high rate of comorbidity. Both disorders are associated with changes in the dopaminergic transmission in the mesocorticolimbic pathways of the brain. Since antipsychotic medications interact with the dopamine receptors in these pathways, these medications could affect craving for substances. In the current study, ...

A series of racemic N-arylalkyl-2-azaadamantan-1-ols (9-15) and the corresponding deoxygenated, achiral N-arylalkyl-2-azaadamantanes (23-29) were synthesized and screened in competition binding assays against a panel of CNS targets. Adamantyl hemiaminals 9-15 displayed generally low affinity for both σ(1) (K(i) values= 294-1950nM) and σ(2) receptors (K(i) values=201-1020nM), and negligible affinity for 42 ...

ET(A) subtype selective antagonists constitute a novel and potentially important class of agents for the treatment of pulmonary hypertension, heart failure, and other pathological conditions. In this paper, 60 benzodiazepine derivatives displaying potent activities against ET(A) and ET(B) subtypes of endothelin receptor were selected to establish the 3D-QSAR models using ...

Dendritic Ca(2+) plays an important role not only in synaptic integration and synaptic plasticity, but also in dendritic excitability in midbrain dopamine neurons. However, the functional organization of dendritic Ca(2+) signals in the dopamine neurons remains largely unknown. We therefore investigated dendritic Ca(2+) signals by measuring glutamate-induced Ca(2+) increases along ...

Background and purpose:  P2 receptors are involved in the regulation of ocular physiological processes like intraocular pressure (IOP). The present study shows the hypertensive effect of the P2Y(2) receptor and how a reduction in IOP is obtained after its silencing. Experimental approach:  Agonists of the P2Y(2) receptor a as well ...

A novel class of imidazo[1,2-a]pyridines as melatonin receptor ligands is designed and synthesized. The affinities of 3-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-N-methyl-propionamide 8, N-[2-(6-methoxy-2-phenylimidazo[1,2-a]pyridine-3-yl)-ethyl]-acetamide 13 and N-(1-hydroxy-3-(5-methoxy-2-phenyl-1H-indol-3-yl)propan-2-yl)acetamide 18 are evaluated for binding on melatonin receptors. Compound 8 present good selectivity for MT(2) over MT(1) (MT(1)/MT(2) = 19) and compound 13 have good affinities for both MT(1) (Ki ...

Considering the significance of progesterone receptor (PR) modulators, the present study is explored to envisage the biophoric signals for binding to selective PR subtype-A using ligand-based quantitative structure activity relationship (QSAR) and pharmacophore space modeling studies on nonsteroidal substituted quinoline and cyclocymopol monomethyl ether derivatives. Consensus QSAR models (Training set ...

A series of 31 analogues of the neolignan honokiol (a major constituent of Magnolia officinalis) was synthesized and their effects on GABAA receptors expressed in Xenopus oocytes were investigated. Honokiol enhanced chloride currents (IGABA) through GABAA receptors of seven different subunit compositions with EC50 values ranging from 23.4 µM (52) ...

Strongly basic groups such as guanidine moieties are crucial structural elements, but they compromise the drug-likeness of numerous biologically active compounds, including ligands of G-protein-coupled receptors (GPCRs). As part of a project focused on the search for guanidine bioisosteres, argininamide-type neuropeptide Y (NPY) Y(2) receptor (Y(2) R) antagonists related to BIIE0246 ...

A novel type of ditopic ion pair receptors based on anion-π interaction is reported. Oxacalix[2]arene[2]triazine azacrowns were synthesized efficiently from a one-pot reaction between 2,4-dichloro-4-methoxytriazine and 3,5-dihydroxybenzaldehyde followed by condensation with a diamine and reduction of bisimine; they acted as selective ditopic receptors to recognize ion pairs.

Entamoeba histolytica is a protozoan parasite that causes amebic dysentery characterized by severe watery diarrhea. Unfortunately, the parasitic factors involved in the pathogenesis of diarrhea are poorly defined. Prostaglandin E(2) (PGE(2)) is a host lipid mediator associated with diarrheal diseases. Intriguingly, E. histolytica produces and secretes this inflammatory molecule. We ...

Previously, we reported that 1 nm 17ß-estradiol (E(2)) induces a rapid action, which is, in part, mediated through the G protein-coupled receptor GPR30 in primate GnRH neurons. Because it has been reported that the diphenylacrylamide compound, STX, causes estrogenic action in the mouse and guinea pig hypothalamus, the present study ...

Based on the pharmacophore model of Glennon the conformationally restricted σ(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5-triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxane 2 in good yields. The 1,3-dioxane 2 represents a ...

In a two-microelectrode voltage clamp with Xenopus laevis oocytes, a petroleum ether extract of Acorus calamus rhizomes enhanced the GABA-induced chloride current through GABA(A) receptors of the α₁β₂γ(2S) subtype by 277% ± 9.7% (100 μg/mL). β-Asarone (1), (+)-dioxosarcoguaiacol (2), (+)-shyobunone (3), and (+)-preisocalamenediol (4) were subsequently identified as main active ...

The 2-fluoroalkoxy substituted catechol-aporphines 6, 8a-f and 11-monohydroxyaporphines 11a-e were synthesized and found to have high in vitro affinity and selectivity for the dopamine D(2) receptors. The catechol aporphines, 8b and 8d, and the monohydroxy aporphines, 11a-d, were identified as candidates for development as potential PET ligands.

Depression is a common comorbidity of temporal lobe epilepsy and has highly negative impact on patients' quality of life. We previously established that pilocarpine-induced status epilepticus (SE) in rats, concurrently with chronic epilepsy leads to depressive impairments, and that the latter may stem from the dysregulation of hypothalamo-pituitary-adrenocortical (HPA) axis ...

A new cannabimimetic phenylacetylindole (cannabipiperidiethanone, 1) has been found as an adulterant in a herbal product which contains two other known synthetic cannabinoids, JWH-122 and JWH-081, and which is distributed illegally in Japan. The identification was based on analyses using GC-MS, LC-MS, high-resolution MS and NMR. Accurate mass spectrum measurement ...

The objectives were to localize estrogen receptor alpha (ERα) and progesterone receptor (PR), and enumerate leukocyte infiltration in cervical tissue of normal bitches during various stages of the estrous cycle (n = 35), as well as in those developing open (n = 22) or closed-cervix pyometra (n = 19). Each ...

Substitutions of the dopamine D(2) or D(3) receptor agonists for the discriminative stimulus effect induced by U-50,488H, methamphetamine (METH) and cocaine in rats were examined. The D(2) receptor agonist R-propylnorapomorphine [(-)-NPA] failed to substitute for U-50,488H cue, while the D(3) receptor-preferred agonist (+/-)-7-hydroxy-dipropylaminotetralin hydrobromide (7-OH-DPAT) produced dose-related increases in drug-appropriate ...

Activation of the newly identified σ₁ chaperone protein is involved in several aspects of the psychostimulant and addictive effects of cocaine. The development of ligands that selectively target the σ₁ protein may lead to putative potent anti-cocaine agents. We report here a new and more convergent synthetic pathway to amino ...

Dysregulation of excitatory synaptic input to nucleus accumbens (NAc) medium spiny neurons (MSNs) underlies a key pathophysiology of drug addiction and addiction-associated emotional and motivational alterations. Dynorphin peptides, which exhibit higher affinity to κ type opioid receptors, are upregulated within the NAc upon exposure to cocaine administration, and the increased ...

Muscarinic acetylcholine receptors in the nucleus accumbens play an important role in mediating the reinforcing effects of cocaine. However, there is a paucity of data regarding the role of accumbal muscarinic acetylcholine receptors in the reinstatement of cocaine-seeking behavior. The goal of these experiments was to assess the role of ...

Competitive dopamine receptor antagonists accelerate psychomotor stimulant self-administration. According to pharmacological theory of competitive antagonism antagonists raise the equiactive agonist concentration. In the self-administration paradigm this is assumed to be the satiety threshold or C(min). The magnitude of the proportional increase in satiety threshold (agonist concentration ratio) as a function ...

It is well known that cocaine blocks the dopamine transporter. This mechanism should lead to a general increase in dopaminergic neurotransmission, and yet dopamine D(1) receptors (D(1)Rs) play a more significant role in the behavioral effects of cocaine than the other dopamine receptor subtypes. Cocaine also binds to σ-1 receptors, ...

Drug addiction processes are considered to be mainly controlled by the mesocorticolimbic dopamine system. Cannabinoids, a class of psychoactive drugs of abuse, elicit their rewarding and pharmacological effects through the endocannabinoid system. Previous research has indicated that dopaminergic neurons in the mesocorticolimbic system are also under the control of the ...

In the present study we examined the effects of cocaine seizure kindling on the expression of NMDA receptors and levels of extracellular glutamate in mouse brain. Quantitative autoradiography did not reveal any changes in binding of [³H] MK-801 to NMDA receptors in several brain regions. Likewise, in situ hybridization and ...

The aim of this study was to investigate whether the δ-opioid receptors are involved in the rewarding and reinstatement effect of cocaine in the conditioned place preference (CPP) test. Male Wistar rats were conditioned with cocaine (5 mg/kg) or saline in a biased CPP procedure. The intracerebroventricular (i.c.v.) administration of naltrindole ...

The globus pallidus plays a critical role in movement regulation. Previous studies have indicated that the globus pallidus receives neurotensinergic innervation from the striatum, and systemic administration of a neurotensin analog could produce antiparkinsonian effects. The present study aimed to investigate the effects of pallidal neurotensin on haloperidol-induced parkinsonian symptoms. ...

Repeated administration of cocaine induces heightened behavioral hyperactivity termed sensitization. Although NK-3 receptors have been shown to modulate acute cocaine-induced behaviors, their role in behavioral sensitization is unknown. The present study investigated whether NK-3 receptor blockade altered behavioral sensitization to cocaine. Additionally, glycogen synthase kinase-3 (GSK3) has been shown to ...

Understanding the psychobiological basis of relapse remains a challenge in developing therapies for drug addiction. Relapse in cocaine addiction often occurs following exposure to environmental stimuli previously associated with drug taking. The metabotropic glutamate receptor, mGluR5, is potentially important in this respect; it plays a central role in several forms ...

This experiment was designed to know whether (-)-epigallocatethin-3-O-gallate (EGCG) counteracts caffeine-induced hyperactivity, and its potential mechanisms in mice. EGCG inhibited methamphetamine-induced, cocaine-induced and caffeine-induced horizontal hyperlocomotion and rearing activity. EGCG also inhibited hyperlocomotion and rearing activity induced by apomorphine, a D1/D2-like agonist. Moreover, EGCG inhibited climbing behavior, a typical stereotyped ...

Dopamine receptors play a critical role in reward-related learning, but receptor subtypes may be differentially involved. D2-preferring receptor antagonists, e.g., haloperidol, attenuate acquisition of cocaine-conditioned motor activity at doses that fail to block expression. We compared haloperidol [4-[4-(4-chlorophenyl)-4-hydroxy-1-piperidyl]-1-(4-fluorophenyl)-butan-1-one] with the D3 receptor-preferring antagonist 2,3-di-tert-butyl-6-{4-[3-(4,5-dimethyl-4H-[1,2,4] triazol-3-yisulfanyl)-propyl]-piperazin-1-y1}-pyrimidine hydrochloride (ABT-127), given at D3 ...

The α-subunit of Go2 is a regulator of dopamine (DA) homeostasis. Deletion of the protein results in an imbalance of the direct and indirect DA pathway by reducing D1 and increasing D2 receptors. As a result, cocaine-induced behavioral sensitization is abolished. Here we show that repeated amphetamine injections in Go2α-/- ...