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PubMed2006

Nested association between genetic variation in tryptophan hydroxylase II, bipolar affective disorder, and suicide attempts.

BACKGROUND: Bipolar affective disorder (BPAD) is a common mental illness that is strongly associated with suicide. Suicidal behavior is thought to result from an interaction of genetic, neurobiological, and psychosocial factors and tends to cluster in families, suggesting specific familial factors distinct from those that underlie BPAD itself. Serotonin signaling has long been implicated in both BPAD and suicide, and the gene encoding the brain-expressed isoform of tryptophan hydroxlyase (TPH2) has been described. Markers in TPH2 have been implicated in suicide and major depressive disorder, but the results across studies are inconsistent. No studies have examined TPH2 in large samples of subjects with BPAD and suicide attempts (SA). We tested for a relationship between genetic variation in TPH2 and risk for BPAD and SA in a large family sample. METHODS: The sample consisted of 2018 members of 670 families, ascertained through a sibling pair affected with bipolar I, bipolar II, or schizoaffective-bipolar disorder and diagnosed under DSM-III/IV criteria. Three single nucleotide polymorphisms representing the common haplotypes spanning TPH2 were analyzed. RESULTS: Single-marker analysis failed to detect significant genetic association with BPAD or SA, but the number of informative families was small. Haplotype analysis showed significant association with both BPAD and SA, and the same haplotype was significantly associated with both BPAD and SA in a replication sample. Case-only analysis, stratified by SA, suggested that TPH2 was not an independent genetic risk factor for SA in this sample. CONCLUSIONS: The TPH2 might contribute to the risk of both BPAD and SA in families with BPAD. Further studies are needed to uncover the functional genetic variation that accounts for the observed associations.

Adult↗

PubMed2006

Neuropsychological functioning in adolescent children of mothers with a history of bipolar or major depressive disorders.

BACKGROUND: Growing evidence demonstrates an association of neuropsychological deficits with mood disorders, but it is not yet clear whether these deficits are risk factors or are concomitant with the symptoms. This study examines the neuropsychological functioning of a group of adolescent offspring who are at risk for a mood disorder by virtue of being raised by mothers who have been diagnosed with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Adolescent offspring of mothers with BPD (n = 43) or MDD (n = 72) and of psychiatrically well parents (n = 50) completed a battery of neuropsychological tests to assess executive functioning, memory, and attention. RESULTS: Children of mothers with BPD showed deficits in executive functioning and selective deficits in spatial memory and attention, in comparison with children of well mothers. Deficits were not found for children of MDD mothers. CONCLUSIONS: Knowledge of these neurocognitive processes could aid ultimately in determining whether neurocognitive deficits precede BPD, whether unique profiles are associated with various types of mood disorders, and who may benefit from interventions.

Adolescent↗

PubMed2006

Attention-deficit/hyperactivity disorder and comorbid disruptive behavior disorders: evidence of pleiotropy and new susceptibility loci.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) comorbid with oppositional defiant disorder (ODD) or conduct disorder (CD) and substance abuse/dependence seems to represent a specific subset within the phenotypic ADHD spectrum. METHODS: We applied complex segregation and linkage analyses in a set of multigenerational families densely segregating ADHD comorbid with ODD, CD, alcohol abuse/dependence, and nicotine dependence. RESULTS: Our data suggest that ADHD cosegregates with disruptive behaviors as a unique, phenotypically variable trait as evidenced by highly significant pair-wise linkages among: ADHD and ODD (logarithm of odds [LOD]=14.19), ADHD and CD (LOD=5.34), ODD and CD (LOD=6.68), and CD and alcohol abuse/dependence (LOD=3.98). In addition to previously reported ADHD susceptibility loci, we found evidence of linkage for comorbid ADHD phenotypes to loci at 8q24, 2p21-22.3, 5p13.1-p13.3, 12p11.23-13.3, 8q15, and 14q21.1-22.2. These results were replicated with an affected status phenotype derived from latent class clusters. CONCLUSIONS: Patterns of cosegregation of ADHD with comorbidities can inform our understanding of the inheritance patterns not only of ADHD but also of disruptive behavioral disorders and alcohol abuse/dependence. Refining the comorbid ADHD phenotype by determining the cosegregation profile of specific comorbidities might be a powerful tool for defining significant regions of linkage.

Adolescent↗

PubMed2006

Disrupted in schizophrenia 1 genotype and positive symptoms in schizophrenia.

BACKGROUND: Converging evidence has demonstrated an association between the Disrupted in Schizophrenia 1 (DISC1) gene and schizophrenia (SZ). Within the DISC1 gene, a single nucleotide polymorphism (SNP), Ser704Cys, has been associated with the structure and function of the hippocampus. Because positive symptoms in SZ have also been associated with hippocampal structure and function, we hypothesized that variation in a DISC1 haplotype containing Ser704Cys would be significantly associated with positive symptomatology in SZ. METHODS: We tested for an association between variation in a haplotype block within the DISC1 gene containing Ser704Cys and lifetime history of positive symptoms in 199 Caucasian patients with SZ. RESULTS: We detected significant associations between a DISC1 haplotype containing Ser704Cys and Ser704Cys genotype and lifetime severity of delusions in SZ. CONCLUSIONS: These data suggest that that the effect of DISC1 genetic variation might be associated with positive symptoms in patients with SZ.

Cysteine↗

PubMed2006

Methamphetamine administration causes death of dopaminergic neurons in the mouse olfactory bulb.

BACKGROUND: Methamphetamine (METH) is an addictive drug that can cause neurological and psychiatric disorders. In the rodent brain, toxic doses of METH cause damage of dopaminergic terminals and apoptosis of nondopaminergic neurons. The olfactory bulb (OB) is a brain region that is rich with dopaminergic neurons and terminals. METHODS: Rats were given a single injection of METH (40 mg/kg) and sacrificed at various time points afterward. The toxic effects of this injection on the OB were assessed by measuring monoamine levels, tyrosine hydroxylase (TH) immunocytochemistry, terminal deoxynucleotidyl transferase-mediated deoxyribonucleotide triphosphate (dNTP) nick end labeling (TUNEL) histochemistry, and caspase-3 immunochemistry. RESULTS: Methamphetamine administration caused marked decreases in dopamine (DA) levels and TH-like immunostaining in the mouse OB. The drug also caused increases in TUNEL-labeled OB neurons, some of which were also positive for TH expression. Moreover, there was METH-induced expression of activated caspase-3 in TH-positive cells. Finally, the METH injection was associated with increased expression of the proapoptotic proteins, Bax and Bid, but with decreased expression of the antideath protein, Bcl2. CONCLUSIONS: These observations show, for the first time, that METH can cause loss of OB DA terminals and death of DA neurons, in part, via mechanisms that are akin to an apoptotic process.

Animals↗

PubMed2005

Preliminary evaluation of the cytotoxicity of a series of tris-2-aminoethylamine (Tren) based hexadentate heterocyclic donor agents.

Tachpyridine is a cytotoxic metal chelator with potential anti-tumor activity. The synthesis and evaluation of a set of derivatives of the related hexadentate heterocyclic donor agents tris-2-aminoethylamine (tren) and tris[N-(2-pyridylmethylene)-2-aminoethyl]amine (trenpyr) was performed to compare their cytotoxic activity to tachpyridine in HeLa tumor cells. Methyl groups were added to the pyridyl ring of trenpyr, and the effects of alkyl group substitution on cell survival were assessed. Profound cytotoxicity was observed and IC50 data were obtained in ascending order from those compounds substituted with a methyl group at the 3-, 4-, or 5-position and lastly by the 6-methyl derivative. These results suggest that analogous derivatives with substitution at the 3-position of the pyridyl ring deserve further exploration.

Cell Survival↗

PubMed2005

Synthesis and structure-activity studies of schweinfurthin B analogs: Evidence for the importance of a D-ring hydrogen bond donor in expression of differential cytotoxicity.

The synthesis and biological evaluation of several enantioenriched schweinfurthin B analogs were undertaken to develop structure-activity relationships and guide design of probes for their putative molecular target. The desired stilbenes contain a common left-half hexahydroxanthene ring system and an aromatic right-half with varied substituents. The synthesis involves penultimate Horner-Wadsworth-Emmons coupling of one of several right-half phosphonates with the aldehyde comprising the left-half of 3-deoxyschweinfurthin B. Preparation of the requisite phosphonates, and the respective stilbenes, as well as the cytotoxicity profiles of these new compounds in the National Cancer Institute's 60 cell-line anticancer screen is described. Several of these analogs displayed cytotoxicity patterns well-correlated with the natural product and differences in activity of approximately 10(3) across the various cell lines. Together, these assay results indicate the importance of at least one free phenol group on the aromatic D-ring of this system for differential cytotoxicity.

Cell Line, Tumor↗

PubMed2005

2-Benzyl and 2-phenyl-3-hydroxypropyl pivalates as protein kinase C ligands.

A series of 2-benzyl and 2-phenyl-3-hydroxypropyl pivalates designed to incorporate the principal pharmacophores of phorbol esters have been synthesized and tested as PKC-alpha ligands. Among the analogues, 13c exhibited the most potent binding affinity with a Ki = 0.7 microM. The synthesized analogues were subjected to molecular modeling analysis based on two alternative models of the phorbol pharmacophore and a docking study of 13c was carried out.

Binding Sites↗

PubMed2006

Synthesis and structure-activity relationships (SARs) of 1,5-diarylpyrazole cannabinoid type-1 (CB(1)) receptor ligands for potential use in molecular imaging.

Cannabinoid type-1 (CB(1)) receptor ligands, derived from the 1,5-diarylpyrazole core template of rimonabant (Acomplia), have been the focus of several studies aimed at examining structure-activity relationships (SARs). The purpose of this study was to design and synthesize a set of compounds based on the 1,5-diarylpyrazole template while focusing on the potential for discovery of CB(1) receptor radioligands that might be used as probes with in vivo molecular imaging. Each synthesized ligand was evaluated for potency as an antagonist at CB(1) and cannabinoid type-2 (CB(2)) receptors in vitro using a GTPgamma(35)S-binding assay. clog P values were calculated with Pallas 3.0. The antagonist binding affinities (K(B)) at CB(1) receptors ranged from 11 to >16,000 nM, CB(1) versus CB(2) selectivities from 0.6 to 773, and clog Ps from 3.61 to 6.25. An interesting new ligand, namely N-(piperidin-1-yl)-1-(2-bromophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxamide (9j), emerged from the synthesized set with appealing properties (K(B)=11 nM; CB(1) selectivity>773; clog P=5.85), for labeling with carbon-11 and development as a radioligand for imaging brain CB(1) receptors in vivo with positron emission tomography (PET).

Drug Design↗

PubMed2006

Design, synthesis, and biological activity of N6-substituted-4'-thioadenosines at the human A3 adenosine receptor.

A large series of N6-substituted-4'-thioadenosines were synthesized starting from D-gulonic-gamma-lactone, and structure-activity relationships were studied at the human A3 and other subtypes of adenosine receptors (ARs). 2-Chloro-substituted and 2-H analogues were compared. 2-Chloro-N6-methyl-4'-thioadenosine 19b was a highly potent and selective agonist (Ki=0.8+/-0.1 nM in binding) at the A3AR, and displayed the same relative efficacy in receptor activation as a known full agonist, Cl-IB-MECA. Most of N6-substituted-4'-thioadenosines were less potent in binding than the corresponding N6-substituted-adenosines or N6-substituted-4'-thioadenosine-5'-uronamides. N6-(3-Iodobenzyl) derivative 19g was demonstrated to be an A3AR-selective partial agonist displaying a Ki value of 3.2 nM.

Adenosine↗

PubMed2006

Synthesis, receptor binding, and activation studies of N(1)-alkyl-L-histidine containing thyrotropin-releasing hormone (TRH) analogues.

Thyrotropin-releasing hormone (TRH) analogues in which the N(1)-position of the imidazole ring of the centrally placed histidine residue is substituted with various alkyl groups were synthesized and studied as agonists for TRH receptor subtype 1 (TRH-R1) and subtype 2 (TRH-R2). Analogue 3 (R=C2H5) exhibited binding affinity (Ki) of 0.012 microM to TRH-R1 that is about 1.1-fold higher than that of TRH. Several analogues were found to selectively activate TRH-R2 with greater potency than TRH-R1. The most selective agonist of the series 5 [R=CH(CH3)2] was found to activate TRH-R2 with a potency (EC50) of 0.018 microM but could only activate TRH-R1 at EC50 value of 1.6 microM; that is, exhibited 88-fold greater potency for TRH-R2 versus TRH-R1. The results of this study indicate that modulation of central histidine residue is important for designing analogues which were selective agonist at TRH receptor subtypes.

Histidine↗

PubMed2006

Transformation of mu-opioid receptor agonists into biologically potent mu-opioid receptor antagonists.

N-Allylation (-CH(2)-CHCH(2)) of [Dmt(1)]endomorphins yielded the following: (i) [N-allyl-Dmt(1)]endomorphin-2 (Dmt=2',6'-dimethyl-l-tyrosine) (12) and [N-allyl-Dmt(1)]endomorphin-1 (15) (K(i)mu=0.45 and 0.26nM, respectively) became mu-antagonists (pA(2)=8.59 and 8.18, respectively) with weak delta-antagonism (pA(2)=6.32 and 7.32, respectively); (ii) intracerebroventricularly administered 12 inhibited morphine-induced CNS-mediated antinociception in mice [AD(50) (0.148ng/mouse) was 16-fold more potent than naloxone], but not spinal antinociception, and (iii) 15 reversed the alcohol-elevated frequency in spontaneous inhibitory post-synaptic currents (IPSC) in hippocampal CA1 pyramidal cells in rat brain slices (P=0.0055). Similarly, N-allylation of the potent mu-opioidmimetic agonists, 1,6-bis-[H-Dmt-NH]-hexane and 3,6-bis-[Dmt-NH-propyl]-2(1H)-pyrazinone, converted them into mu-antagonists (pA(2)=7.23 and 7.17 for the N-allyl-derivatives 17 and 19, respectively), and exhibited weak delta-antagonism. Thus, N-allylation of Dmt containing opioid peptides or opioidmimetics continues to provide a facile means to convert selective mu-opioid agonists into potent mu-opioid antagonists.

Alkylation↗

PubMed2005

New series of potent delta-opioid antagonists containing the H-Dmt-Tic-NH-hexyl-NH-R motif.

Heterodimeric compounds H-Dmt-Tic-NH-hexyl-NH-R (R=Dmt, Tic, and Phe) exhibited high affinity to delta- (K(i)delta=0.13-0.89nM) and mu-opioid receptors (K(i)mu=0.38-2.81nM) with extraordinary potent delta antagonism (pA(2)=10.2-10.4). These compounds represent the prototype for a new class of structural homologues lacking mu-opioid receptor-associated agonism (IC(50)=1.6-5.8muM) based on the framework of bis-[H-Dmt-NH]-alkyl (Okada, Y.; Tsuda, Y.; Fujita, Y.; Yokoi, T.; Sasaki, Y.; Ambo, A.; Konishi, R.; Nagata, M.; Salvadori, S.; Jinsmaa, Y.; Bryant, S. D.; Lazarus, L. H. J. Med. Chem.2003, 46, 3201), which exhibited both high mu affinity and bioactivity.

Animals↗

PubMed2006

Synthesis of 3,6-bis[H-Tyr/H-Dmt-NH(CH2)m,n]-2(1H)pyrazinone derivatives: function of alkyl chain length on opioid activity.

Dimeric opioid analogues linked to a pyrazinone platform, 3-[Tyr/Dmt-NH(CH2)m]-6-[Tyr/Dmt-NH(CH2)n]-2(1H)-pyrazinone (m, n=3 or 4), were synthesized. The Tyr-containing compound (m=4, n=3) exhibited mu-receptor affinity (K(i)mu; 7.58 nM) comparable to that of morphine, while the Dmt derivatives exhibited considerably higher affinity (K(i)mu; 0.021-0.051 nM) with corresponding agonism (IC50=1.79-4.93 nM). Interestingly one compound (m=4, n=3) revealed modest delta-opioid agonism; the converse analogue (m=3, n=4), however, was inactive in MVD assay.

Animals↗

PubMed2006

Halogenation of 4-hydroxy-3-methoxybenzyl thiourea TRPV1 agonists showed enhanced antagonism to capsaicin.

Selected potent TRPV1 agonists (1-6) have been modified by 5- or 6-halogenation on the aromatic A-region to analyze their effects on potency and efficacy (agonism versus antagonism). The halogenation caused enhanced functional antagonism at TRPV1 compared to the corresponding prototype agonists. The analysis of SAR indicated that the antagonism was enhanced as the size of the halogen increased (I>Br>Cl) and when the 6-position was halogenated. Compounds 23c and 31b were found to be potent full antagonists with K(i) (as functional antagonist)=23.1 and 30.3 nM in rTRPV1/CHO system, respectively.

Animals↗

PubMed2006

Synthesis and HIV-1 integrase inhibitory activity of spiroundecane(ene) derivatives.

Fifteen 2,4-dioxaspiro[5.5]undecane ketone and 2,4-dioxa-spiro[5.5]undec-8-ene (spiroundecane(ene)) derivatives were synthesized using the Diels-Alder reaction. Inhibition of human immunodeficiency virus integrase (IN) was examined. Eight spiroundecane(ene) derivatives inhibited both 3'-processing and strand transfer reactions catalyzed by IN. SAR studies showed that the undecane core with at least one furan moiety is preferred for IN inhibition. Moreover, crosslinking experiments showed that spiroundecane derivatives did not affect IN-DNA binding at concentrations that block IN catalytic activity, indicating spiroundecane derivatives inhibit preformed IN-DNA complex. The moderate toxicity of spiroundecane(ene) derivatives encourages the further design of therapeutically relevant analogues based on this novel chemotype of IN inhibitors.

Alkanes↗

PubMed2006

Skeletal site-specific characterization of orofacial and iliac crest human bone marrow stromal cells in same individuals.

Autologous grafts from axial and appendicular bones commonly used to repair orofacial bone defects often result in unfavorable outcome. This clinical observation, along with the fact that many bone abnormalities are limited to craniofacial bones, suggests that there are significant differences in bone metabolism in orofacial, axial and appendicular bones. It is plausible that these differences are dictated by site-specificity of embryological progenitor cells and osteogenic properties of resident multipotent human bone marrow stromal cells (hBMSCs). This study investigated skeletal site-specific phenotypic and functional differences between orofacial (maxilla and mandible) and axial (iliac crest) hBMSCs in vitro and in vivo. Primary cultures of maxilla, mandible and iliac crest hBMSCs were established with and without osteogenic inducers. Site-specific characterization included colony forming efficiency, cell proliferation, life span before senescence, relative presence of surface markers, adipogenesis, osteogenesis and transplantation in immunocompromised mice to compare bone regenerative capacity. Compared with iliac crest cells, orofacial hBMSCs (OF-MSCs) proliferated more rapidly with delayed senescence, expressed higher levels of alkaline phosphatase and demonstrated more calcium accumulation in vitro. Cells isolated from the three skeletal sites were variably positive for STRO 1, a marker of hBMSCs. OF-MSCs formed more bone in vivo, while iliac crest hBMSCs formed more compacted bone that included hematopoietic tissue and were more responsive in vitro and in vivo to osteogenic and adipogenic inductions. These data demonstrate that hBMSCs from the same individuals differ in vitro and in vivo in a skeletal site-specific fashion and identified orofacial marrow stromal cells as unique cell populations. Further understanding of site-specific properties of hBMSCs and their impact on site-specific bone diseases and regeneration are needed.

Adolescent↗

PubMed2006

Correlates of bone quality in older persons.

PURPOSE OF THE STUDY: In a population-based sample of older persons, we studied the relationship between tibial bone density and geometry and factors potentially affecting osteoporosis. METHODS: Of the 1260 participants aged 65 years or older eligible for the InCHIANTI study, 1155 received an interview and 915 (79.2%) had complete data on tibial QCT scans and other variables used in the analysis presented here. The final study population included 807 persons (372 men and 435 women, age range 65-96 years) after exclusion of participants affected by bone diseases or treated with drugs that interfere with bone metabolism. RESULTS: In both sexes, calf cross-sectional muscle area (CSMA) was significantly and independently associated with total bone cross-sectional area (tCSA) and cortical bone cross-sectional area (cCSA) but not with trabecular or cortical volumetric bone mineral density (vBMD). Bioavailable testosterone (Bio-T) was independently associated with both trabecular and cortical vBMD in both sexes. In women, independently of confounders, 25(OH)-vitamin D was positively associated with tCSA and cortical vBMD, while PTH was negatively associated with cortical vBMD. IL-1 beta was negatively correlated with cortical vBMD in women, while TNF-alpha was associated with enhanced bone geometrical adaptation in men. CONCLUSIONS: Physiological parameters that are generically considered risk factors for osteoporosis were associated with specific bone parameters assessed by tibial QCT. Factors known to be associated with increased bone reabsorption, such as 25(OH)-vitamin D, PTH and Bio-T, affected mainly volumetric BMD, while factors associated with bone mechanical stimulation, such as CSMA, affected primarily bone geometry. Our results also suggested that pro-inflammatory cytokines might be considered as markers of bone resorption.

Aged↗