Dibenzazecine scaffold rebuilding—Is the flexibility always essential for high dopamine receptor affinities?

The moderately flexible 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are known to be potent dopamine receptor antagonists, whereas the corresponding rigid dibenzo[d,g]quinolizines are inactive. We built the scaffolds of dibenzo[c,g], [c,f] and [d,f]azecines and together with their ring closed, more rigid precursors, evaluated the affinities for the human D₁–D₅ receptors (radioligand binding) as well as the functionalities (calcium assay) and thus investigated the influence of annelation and conformative flexibility of these compounds on their affinity for human cloned dopamine receptors.     

Synthesis and characterization of selective dopamine D₂ receptor ligands using aripiprazole as the lead compound

A series of compounds structurally related to aripiprazole (1), an atypical antipsychotic and antidepressant used clinically for the treatment of schizophrenia, bipolar disorder, and depression, have been prepared and evaluated for affinity at D(?-like) dopamine receptors. These compounds also share structural elements with the classical D(?-like) dopamine receptor antagonists, haloperidol, N-methylspiperone, domperidone and benperidol. Two new compounds, 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (6) and 7-(4-(4-(2-(2-fluoroethoxy)phenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one oxalate (7) were found to (a) bind to the D? receptor subtype with high affinity (K(i) values < 0.3 nM), (b) exhibit >50-fold D? versus D? receptor binding selectivity and (c) be partial agonists at both the D? and D? receptor subtype.     

Is GPR146 really the receptor for proinsulin C-peptide?

Proinsulin C-peptide has previously been proposed to interact with a G-protein coupled receptor (GPCR), specifically the orphan receptor GPR146. To investigate the potential of C-peptide in treating complications of diabetes, such as kidney damage, it is necessary to understand its mode of action. We used CHO-K1 cells expressing human GPR146 to study human and murine C-peptide in dynamic mass redistribution and GPCR β-arrestin assays, as well as with fluorescence confocal microscopy. Neither assay revealed any significant intracellular response to C-peptide at concentrations of up to 33 µM. We observed no internalisation of C-peptide by fluorescence microscopy. Our results do not support GPR146 as the receptor for C-peptide, but suggest that further investigations of the mode of action of C-peptide should be undertaken.     

Diazaspirocyclic compounds as selective ligands for the α4β2 nicotinic acetylcholine receptor

Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (K(i)>500 nM).     

Where is the vitamin D receptor?

The vitamin D receptor (VDR) is a member of the nuclear receptor superfamily and plays a central role in the biological actions of vitamin D. VDR regulates the expression of numerous genes involved in calcium/phosphate homeostasis, cellular proliferation and differentiation, and immune response, largely in a ligand-dependent manner. To understand the global function of the vitamin D system in physiopathological processes, great effort has been devoted to the detection of VDR in various tissues and cells, many of which have been identified as vitamin D targets. This review focuses on the tissue- and cell type-specific distribution of VDR throughout the body.     

Is the Arg-Gly-Asp sequence the site for foot-and-mouth disease virus binding with cell receptor?

The Arg-Gly-Asp sequence is being found in an increasing wide range of proteins with "adhesive" function. Studying a series of synthetic peptide fragments of VP1 protein of FMDV, we showed that peptides containing the Arg-Gly-Asp sequence, but not control peptides, inhibited FMDV binding to pig kidney cells in vitro, thus indicating participation of that sequence in FMDV binding to host cells.     

The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor β to stimulate ERK1/2

Dopamine receptors are GPCRs that play important roles in locomotion, reward, and cognitive processes. Previously, we demonstrated that this receptor transactivates PDGFRβ to modulate ERK1/2 and NMDA receptor activity. Downregulation of maturely glycosylated PDGFRβ by prolonged exposure to PDGF-BB eliminated PDGF-BB-mediated ERK1/2 activation. The DRD4-mediated ERK1/2 response was only partially blunted by PDGF-BB-mediated downregulation, but remained sensitive to the PDGFRβ kinase inhibitor tyrphostin A9. Tunicamycin prevented the N-linked glycosylation and maturation of PDGFRβ as well as its activation by PDGF-BB. However, upon tunicamycin treatment, DRD4 continued to signal to ERK1/2 in a tyrphostin A9-sensitive manner. Collectively, our observations indicate that DRD4, unlike PDGF-BB, can activate a pool of intracellularly located PDGFRβ.     

Assortative versus selective mating: Is the distinction worthwhile?

Abstract

The study examines the distinction between assortative and selective mating made by Lewontin, Kirk, and Crow in 1968 and finds it unproductive. Not only has the difference been ignored on many occasions even as it was invoked, but maintaining it obscures several useful properties of both nonrandom mating schemes and some formally equivalent systems such as fertility selection. The elucidation of these similarities could have accelerated the work of population biologists.     

Determination of key receptor–ligand interactions of dopaminergic arylpiperazines and the dopamine D2 receptor homology model

Interest in structure-based G-protein-coupled receptor (GPCR) ligand discovery is huge, given that almost 30 % of all approved drugs belong to this category of active compounds. The GPCR family includes the dopamine receptor subtype D2 (D2DR), but unfortunately—as is true of most GPCRs—no experimental structures are available for these receptors. In this publication, we present the molecular model of D2DR based on the previously published crystal structure of the dopamine D3 receptor (D3DR). A molecular modeling study using homology modeling and docking simulation provided a rational explanation for the behavior of the arylpiperazine ligand. The observed binding modes and receptor–ligand interactions provided us with fresh clues about how to optimize selectivity for D2DR receptors.

Discovery of selective indole-based prostaglandin D₂ receptor antagonist

A series of N-benzoyl-2-methylindole-3-acetic acids were synthesized and biologically evaluated as prostaglandin (PG) D? receptor antagonists. Some of the selected compounds significantly inhibited OVA-induced vascular permeability in guinea pig conjunctiva after oral dosing. Structure-activity relationship study is presented.     

Is GPR39 the natural receptor of obestatin?

GPR39, an orphan receptor belonging to the family of G protein-coupled receptors, was originally reported to be the receptor of obestatin. However recently, numerous reports have questioned this conclusion. In mammals, GPR39 was reported to be involved in the regulation of gastrointestinal and the metabolic functions. In this article, a latest and brief review on the receptor family, structure, distribution and physiological functions of GPR39 has been reported.     

Design, synthesis, and pharmacological evaluation of novel tetrahydroprotoberberine derivatives: selective inhibitors of dopamine D₁ receptor

A series of new tetrahydroprotoberberine (THPB) derivatives were designed, synthesized, and tested for their binding affinity towards dopamine (D(1) and D(2)) and serotonin (5-HT(1A) and 5-HT(2A)) receptors. Many of the THPB compounds exhibited high binding affinity and activity at the dopamine D(1) receptor, as well as high selectivity for the D(1) receptor over the D(2), 5-HT(1A), and 5-HT(2A) receptors. Among these, compound 19c exhibited a promising D(1) receptor binding affinity (K(i)=2.53nM) and remarkable selectivity versus D(2)R (inhibition=81.87%), 5-HT(1A)R (inhibition=61.70%), and 5-HT(2A)R (inhibition=24.96%). Compared with l-(S)-stepholidine (l-SPD) (D(1)K(i)=6.23nM, D(2)K(i)=56.17nM), compound 19c showed better binding affinity for the D(1) receptor (2.5-fold higher) and excellent D(2)/D(1) selectivity. Functional assays found compounds 18j, 18k, and 19c are pure D(1) receptor antagonists. These results indicate that removing the C10 hydroxy group and introducing a methoxy group at C11 of the pharmacophore of l-SPD can reverse the function of THPB compounds at the D(1) receptor. These results are in accord with molecular docking studies.     

Is dopamine important in nicotine dependence?

Nicotine, like other drugs when abused, can produce a wide array of behaviours, some of which collectively propel ‘drug-seeking behaviour’. This review focuses on three stimulus properties of nicotine and examines the role of dopamine in mediating each affect with respect to D1 and D2 receptor subtypes. Dopamine appears to be critical in mediating the reinforcing effects of nicotine, which is in line with other commonly abuse psychomotor stimulants. However, evidence derived from studies with local microinjections of nicotine suggests that the origin of nicotine action to produce its other stimulus properties may be via multiple neuroanatomical substrates. The aversive simulus effects are resistant to dopamine receptor antagonists. The discriminative stimulus effects of nicotine, despite showing some modification with dopaminergic compounds, appear not to be solely mediated via the mesolimbic dopamine system. Taken together, the neurobiology of nicotine dependence remains complex. Nonetheless, such association between stimulus properties may permit the development of more effective therapies in combating tobacco dependence.     

Is receptor oligomerization causally linked to activation of the EGF receptor kinase?

Transduction of a signal from an extracellular peptide hormone to produce an intracellular response is often mediated by a cell surface receptor, which is usually a glycoprotein. The secondary intracellular signal(s) generated after hormone binding to the receptor have been intensively studied. The nature of the primary signal generated by ligand binding to the receptor is understood less well in most cases. The particular case of the epidermal growth factor (EGF) receptor is analyzed, and evidence for or against two dissimilar models of primary signal transduction is reviewed. Evidence for the most widely accepted current model is found to be unconvincing. Evidence for the other model is substantial but indirect; a direct test of this model remains to be done.     

Is 1,25-dihydroxyvitamin D required for reproduction?

The role of 1,25-dihydroxyvitamin D (1,25-(OH)2D) in avian and mammalian reproduction is examined. 1,25-Dihydroxyvitamin D is required, in both the avian and mammalian species, for maintenance of normocalcemia, adequate intestinal calcium absorption, bone turnover, and mineral homeostasis throughout the reproductive cycle--just as it is required in the nonlaying bird or nonpregnant, nonlactating mammal. In the avian species, 1,25-(OH)2D is required for ovulation and shell formation, transfer of calcium from the egg shell across the chorioallantoic membrane to the fetal circulation, and maintenance of fetal serum calcium, bone metabolism, and mineral homeostasis. In the mammalian species, 1,25-(OH)2D is required for normal ovulation, normal fetal and neonatal bone metabolism, milk production, and maintenance of normocalcemia and mineral homeostasis in the neonate. In the absence of 1,25-(OH)2D, however, embryogenesis (rat and chick) and neonatal development (rat) can proceed in such a way as to produce viable, normal appearing offspring. The classical effects of 1,25-(OH)2D deficiency (hypocacemia, inadequate intestinal calcium absorption, and bone mineralization) become increasingly apparent with advancing age but there are no other apparent major developmental abnormalities.     

Is morphine dependence mediated exclusively by the Mu receptor?

Regional cerebral glucose utilization (RCGU) and behavior during naloxone precipitated withdrawal were studied in rats made dependent on either sufentanil, a highly selective mu opiate agonist, or morphine. Changes in RCGU during withdrawal in 23 of 24 anatomically related limbic and brainstem structures were indistinguishable between rats dependent on morphine or sufentanil. Linear regression analysis indicated that RCGU changes during withdrawal in these two groups were highly correlated (r=0.95). Withdrawal behaviors (autonomic signs of withdrawal, jumps, weight loss, and incidence of diarrhea) were likewise indistinguishable between the two groups. The correlations of both these measurements of dependence suggest that chronic occupation of mu opiate receptors alone is sufficient to produce dependence that is indistinguishable from morphine dependence.     

Is there a rationale for neuroprotection against dopamine toxicity in Parkinson's disease?

Parkinson's disease is a progressive neurological disease caused by rather selective degeneration of the dopaminergic neurons in the substantia nigra. Though subject to intensive research, the etiology of this nigral loss is still undetermined and treatment is basically symptomatic. The current major hypothesis is that nigral neuronal death in PD is due to excessive oxidative stress generated by auto and enzymatic oxidation of the endogenous neurotransmitter dopamine (DA), the formation of neuromelanin (NM) and the presence of a high concentration of iron. In this review article although we concisely describe the effects of NM and iron on neuronal survival, we mainly focus on the molecular mechanisms of DA-induced apoptosis. DA exerts its toxic effects through its oxidative metabolites either in vitro or in vivo The oxidative metabolites then activate a very intricate web of signals, which culminate in cell death. The signal transduction pathways and genes, which are associated with DA toxicity are described in detail.     

Is Vitamin D the Fountain of Youth?

ObjectiveTo review the role of vitamin D deficiency for both classic and “nonclassic” effects and raise the caution that association does not prove causation.MethodsThe pertinent literature regarding vitamin D and its effects on bone, muscle function, immune function, glucose tolerance, cancer risk, and development of cardiovascular disease and other conditions is reviewed. In addition, the limitations of observational studies are discussed.ResultsVitamin D inadequacy is common worldwide and classically causes osteomalacia and rickets. More recently, the contribution of low vitamin D status to increased falls and fracture risk has become appreciated. Additionally, nonclassic effects of vitamin D inadequacy are being recognized, and low vitamin D status is being potentially associated with a multitude of conditions (including Alzheimer disease, osteoarthritis, multiple sclerosis, and hypertension) and higher overall mortality. It is important to recognize that associations in observational studies can be due to chance, bias, or confounders or may be indicative of causality.ConclusionBecause vitamin D deficiency has been established to have adverse musculoskeletal consequences, optimization of vitamin D status, for both the individual patient and the overall population, is indicated. (Endocr Pract. 2009;15:590-596)