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At least 1,621 records · Page 90Linked to original sources
PubMed1994

Is SDZ NVI-085 an alpha 1-adrenoceptor subtype-selective agonist?

SDZ NVI-085 has been proposed to be a centrally acting agonist with selectivity for some alpha 1-adrenoceptor subtypes. We have investigated its selectivity and efficacy at alpha 1-adrenoceptor subtypes in rat tissues and at cloned subtypes. SDZ NVI-085 had higher affinity for chloro-ethylclonidine-insensitive (alpha 1A-like) than for -sensitive (alpha 1B) alpha 1-adrenoceptors in rat kidney but not in cerebral cortex. SDZ NVI-085 recognized cloned alpha 1-adrenoceptor subtypes expressed in COS cells with the order of potency bovine alpha 1C > rat alpha 1A/D > rat alpha 1B. Relative to 100 microM noradrenaline, SDZ NVI-085 was only a partial agonist for stimulation of inositol phosphate formation in rat kidney and inhibited noradrenaline-stimulated inositol phosphate formation in native and chloroethylclonidine-treated tissue. We conclude that SDZ NVI-085 discriminates among multiple alpha 1-adrenoceptor subtypes and is a partial agonist at rat renal alpha 1A- and alpha 1B-adrenoceptors.

Adrenergic alpha-Agonists↗
PubMed1994

Bradykinin receptor types and B2 subtypes.

Bradykinin, desArg9BK, some agonist analogues and several antagonists have been tested in isolated organs in order to identify bradykinin B2 receptor subtypes. The initial pharmacological characterization was made in the rabbit jugular vein and the guinea pig ileum, two widely used B2 preparations which have shown marked differences in their sensitivities to both agonists and antagonists. The study has then been extended to peripheral tissues (stomach, colon, urinary bladder) of four species (the rat, guinea pig, rabbit and man) and to isolated vessels (rabbit jugular vein, rabbit vena cava, guinea pig pulmonary artery, rat portal vein) in order to determine if pharmacologic receptor subtypes may be related to species. It has been shown that B2 receptors in rat and guinea pig tissues belong to a similar pharmacological entity, a receptor which is different from that mediating the responses of rabbit and human tissues. Agonists order of potency ([Hyp3]BK > BK > [Aib7]BK) obtained in the rabbit jugular vein is different from that found in the guinea pig ileum (BK < or = [Aib7]BK > [Hyp3]BK). Affinities of competitive antagonists (for instance DArg[Hyp3,DPhe7,Leu8]BK) in rabbit tissues are higher than in guinea pig and rat tissues by at least 2 log units, while the non peptidic compound WIN 64338 is more active (also by two log units) in guinea pig than in human and rabbit tissues. The non competitive long-acting antagonist HOE 140 is very potent and equally active in the four species. Some antagonists (peptides without unnatural residues, peptides with unnatural residues, non peptides) have been shown to be specific for kinin receptors and selective for the B2. Altogether, the present results a) confirm the existence of two B2 receptor subtypes, b) suggest that receptor subtypes may be species dependent and c) indicate that the B2 receptor subtype found in the rabbit is similar to that found in man.

Animals↗
PubMed1995

The alpha 1d-adrenoceptor subtype is involved in the noradrenaline-induced contractions of rat aorta.

The pA2 value of several alpha 1-adrenoceptor antagonists on noradrenaline-induced contractions of rat aorta, and their affinity for the cloned alpha 1a-, alpha 1b- and alpha 1d-adrenoceptor subtypes were evaluated. Selective or moderately selective alpha 1d-, partially selective alpha 1b-, selective alpha 1a- and non subtype-selective alpha 1-adrenoceptors antagonists were included in the study. The potency of these compounds on rat aorta was well correlated with the affinity observed for the alpha 1d-adrenoceptor subtype. A poor correlation was found for the alpha 1b- and alpha 1a-subtypes. These results suggest that the alpha 1d-subtype plays a determining role in rat aorta contractions induced by noradrenaline.

Adrenergic alpha-Antagonists↗
PubMed1994

Retrotrapezoid nucleus muscarinic receptor subtypes localized by autoradiography.

Microinjection of muscarinic receptor subtype antagonists into the region of the cat retrotrapezoid nucleus (RTN) decreases blood pressure (greatest efficacy; M2 subtype) and both baseline phrenic activity and CO2 sensitivity (greatest efficacy; M3/M1 subtype). Here we examine, in cat medullary sections at the level of the RTN, the effects of the same antagonists on binding of the high affinity muscarinic agonist quinuclidinyl benzilate (QNB). 3H-QNB binding was saturated and highly specific at 1 nM concentration and stable over 30 to 120 min (Kd, 0.49 nM; Bmax, 136 fm/mg protein). Studied biochemically, we found IC50 values for whole sections of 4.9 x 10(-6) M (M1 antagonist pirenzepine); 1.0 x 10(-6) M (M2 antagonist AFDX); and 0.64 x 10(-7) M (M3 antagonist DAMP; P < 0.03 vs PZ). Densitometric analysis of whole medullary cross section autoradiograms resulted in similar IC50 values as in the biochemical approach. Specific analysis of the RTN region demonstrated the presence of 3H-QNB binding and similar competition by the antagonists. Average IC50 values determined by densitometry were 14 x 10(-6) M (pirenzepine); 1.3 x 10(-6) M (AFDX; P < 0.01 vs PZ); and 0.53 x 10(-7) M (DAMP; P < 0.01 vs PZ). All three subtypes of muscarinic receptors identifiable via pharmacological antagonists appear to be present in the RTN region but we could not distinguish a subtype-specific pattern of receptor distribution.

Adamantane↗
PubMed1988

Imidazopyridines as a tool for the characterization of benzodiazepine receptors: a proposal for a pharmacological classification as omega receptor subtypes.

At present, the nomenclature of benzodiazepine (BZ) receptors is based on its historical association with the BZ structure. However, it is mainly through the new compounds chemically unrelated to BZs that the central and peripheral subtypes of BZ receptors have been characterized. We therefore propose the nomenclature of a greek letter omega, as omega 1, omega 2 and omega 3 to designate respectively the central BZ1, BZ2 and the peripheral BZ receptor. Among the several classes of non-BZ drugs with affinity for different receptors, the imidazopyridines provide a valuable tool for the characterization of omega receptor subtypes. Most BZs are non selective ligands for the central omega 1 and omega 2 receptors while the selectivity for omega 1 receptor subtypes is present in several non BZ chemical series: imidazopyridines (zolpidem), triazolopyridazines (CL 218872), betacarbolines (beta-CCE) and pyrazoloquinolines (CGS 8216). Selective ligands for the omega 2 subtype are not available so far. The so called peripheral BZ receptor is also present in the central nervous system, therefore the proposed nomenclature of omega 3 receptors resolves this paradox because it does not designate location and it is defined in terms of pharmacological specificity. Selective ligands for omega 3 receptors include the BZ Ro 5-4864, and the isoquinolinecarboxamide PK 11195, while the imidazopyridine alpidem is the ligand with the highest affinity for this receptor subtype.

Animals↗
PubMed1992

Differential localization of alpha 2-adrenergic receptor subtypes in brain.

The pharmacological identification and characterization of subtypes of alpha 2-adrenergic receptors have been confirmed by molecular biological investigations. Using receptor autoradiographic techniques, it has been possible to show regions of the brain where alpha 2 agonist binding ([3H]para-aminoclonidine) is preferentially labeling the presumed guaninenucleotide-sensitive, high-affinity conformations of the alpha 2 receptor. Careful examination of autoradiograms generated using the tritiated antagonists yohimbine, idazoxan, and rauwolscine also indicates some disparity in the regions occupied by these radiolabeled ligands. Inhibition of [3H]rauwolscine binding with the subtype selective compounds, ARC-239, or oxymetazoline demonstrates that there are discrete regions of the brain where one receptor subtype predominates over the other. These studies indicate that previous investigations utilizing the agonist para-aminoclonidine as the ligand for obtaining labeling of alpha 2 receptors have overlooked some regions of binding due to the subtype selectivity of this ligand. A more complete localization of alpha 2-adrenergic receptors can be obtained using the tritiated antagonist rauwolscine, and the differential distribution of at least two subtypes of the alpha 2 receptor can be obtained by selective inhibition of this binding.

Adrenergic alpha-Agonists↗
PubMed1991

HLA class I typing by PCR: HLA-B27 and an African B27 subtype.

We describe a rapid method of HLA class I typing using the polymerase chain reaction and oligonucleotide hybridisation that eliminates the requirements for viable lymphocytes and allows subtypes to be defined. We have used this to demonstrate that the predominant subtype of HLA-B27 in the Gambia, West Africa, is HLA-B*2703, which is very rare or absent in other racial groups. This subtype differs from the common Caucasian HLA-B27 subtypes in its recognition by cytotoxic T cells. We propose that HLA*B-2703, unlike other HLA-B27 subtypes, may not be associated with ankylosing spondylitis, thus accounting in part for the rarity of this condition in black populations.

Adult↗
PubMed1994

Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes.

Recent research in molecular biology has demonstrated the complexity of GABAA receptors and shown that benzodiazepine (BZ-omega) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazepines (anticonvulsant activity, anxiety reduction, motor incoordination, learning deficits, characteristic discriminative stimulus effects, tolerance and dependence) are associated with activity at different receptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (omega) receptor ligands relevant to the question of the functional significance of the BZ1 (omega 1) and BZ2 (omega 2) receptor subtypes. The only drugs currently available with a considerable degree of selectivity are alpidem and zolpidem. These compounds have relatively high affinity for GABAA receptors containing the alpha 1 subunit (corresponding to the BZ1 (omega 1) subtype) and very low affinity for receptors with the alpha 5 subunit (corresponding to one type of BZ2 (omega 2) receptor). Pharmacological effects observed with these, and other, less selective compounds allow several tentative conclusions to be drawn: (a) Little is known of the role of subtype selectivity in anxiolytic or amnestic effects but compounds with low intrinsic activity may reduce anxiety without giving rise to sedation or motor incoordination and BZ1 (omega 1) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ1 (omega 1) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ2 (omega 2) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of different BZ (omega) receptor ligands are not identical and differences may be related to receptor selectivity; (d) Compounds with BZ1 (omega 1) selectivity and compounds with low intrinsic activity produce little or no tolerance and dependence. A wider range of selective compounds will be necessary to investigate these factors in detail and many different pharmacological profiles can be expected from drugs with selectivity and different levels of intrinsic activity.

Animals↗
PubMed1994

Alpha 2-adrenoceptors: more subtypes but fewer functional differences.

The proliferation of receptor subtypes based on differences in amino acid sequence does not necessarily coincide with functional differences. The number of alpha 2-adrenoceptor subtypes, as defined by ligand-binding and molecular studies, has been increasing in the past few years, which suggests the possibility of distinct physiological and pathological pathways that could be targeted by new selective drugs. However, the evidence from functional studies has been less convincing. This could be due to the lack of sufficiently selective ligands or to the similarity between the activated state of receptor subtypes. Species differences and the local receptor environment are also important determinants of the pharmacological profile of a particular subtype. The pharmacology of the putative subtypes of alpha 2-adrenoceptors and their function are discussed in this review by Alison MacKinnon, Mike Spedding and Christine Brown.

Adrenergic alpha-Antagonists↗
PubMed1992

Stable expression of recombinant human alpha 2-adrenoceptor subtypes in two mammalian cell lines: characterization with [3H]rauwolscine binding, inhibition of adenylate cyclase and RNase protection assay.

Cloning of the genes encoding distinct subtypes of human alpha 2-adrenergic receptors (alpha 2-AR) allows the separate recombinant expression of each individual subtype in heterologous systems. We report here the transfection, selection and preliminary pharmacological characterization of two mammalian cell lines, adherent Shionogi S115 mouse mammary tumour cells and human B-lymphoblastoid IBW4 cells growing in suspension, expressing the human alpha 2-AR subtypes alpha 2-C4 and alpha 2-C10 at densities of approx. 2 x 10(5) receptors/cell. Transfection of the subtype genes was verified using a specific RNase protection assay. Pharmacological characterization was carried out with [3H]rauwolscine binding, which was inhibited by oxymetazoline and prazosin in a subtype-selective manner. The sensitivity of (-)-noradrenaline binding to the GTP-analogue 5'-guanylylimidodiphosphate suggested that the receptors are coupled to G-proteins. This was verified in S115 cells by efficient inhibition of forskolin-stimulated cAMP production by the alpha 2-AR agonists, (-)-noradrenaline and clonidine. These cell lines thus appear to be suitable for pharmacological studies on receptor function and ligand binding.

Adenylyl Cyclase Inhibitors↗
PubMed1988

Formation of mixed hemagglutinin trimers in the course of double infection with influenza viruses belonging to different subtypes.

Chick embryo primary cultured cells were infected with influenza viruses belonging to H1, H2, H3, H5 or H7 subtypes of hemagglutinin. The cells were subjected to a single or a double infection, labelled with 14C-amino acids from 2 to 6 hours postinfection, lysed with a mixture of ionic and non-ionic detergents, and the lysates were clarified by low-speed centrifugation. The clarified lysates contained 14C-labelled hemagglutinin mostly in the form of 9S trimers, as shown by velocity sedimentation in sucrose gradients with polyacrylamide gel electrophoresis (PAGE) analysis of the gradient fractions. The lysates were immunoprecipitated with antihemagglutinin antibodies specific for one of the co-infecting viruses. The immunoprecipitates were analysed by PAGE. Cells infected separately with each virus and mixed before lysis were used as a control sample in every experiment. In the lysates of cells doubly infected with H2 and H5 influenza viruses the analysis revealed the presence of structures containing HA monomers of both viruses, whereas no such structures were revealed in the lysate of a mixture of separately infected cells. Mixed structures (most likely HA trimers containing monomers of the two co-infecting viruses) were also found in the lysates of cells doubly infected with strains belonging to H1 and H2 subtypes. No such structures were revealed when the cells were co-infected with viruses belonging to H1 and H3 subtypes or H3 and H7 subtypes. The results suggest an extensive formation of mixed HA trimers in the course of double infection with viruses belonging to closely related subtypes, whereas the formation of mixed trimers by more distantly related HA monomers does not occur or is very scarce. The identity of the mixed structures as HA trimers was confirmed by immunoprecipitation experiments with 9S structures.

Amino Acid Sequence↗
PubMed1995

Classification of hepatitis C virus into major types and subtypes based on molecular evolutionary analysis.

Molecular evolutionary analysis was applied to determine the number of hepatitis C virus (HCV) types and subtypes based on all the HCV nucleotide sequences available from the DNA data banks (DDBJ, GenBank (NCBI), EMBL) and the literature. There was an excellent concordance among the types and subtypes assigned based on different HCV genomic regions. Only one HCV isolate was assigned to different HCV types based on the 5' non-coding (NC) and envelope 1 (E1) regions. The 5' NC region was well conserved and could be used to assign only types and not subtypes. From the sequence data available there were 13 subtypes based on the core region and 14 subtypes based on the E1 and non-structural protein 5 (NS5) regions.

Biological Evolution↗
PubMed1995

Relationship between hepatitis C virus subtypes and clinical features of liver disease seen in alcoholics.

The influence of hepatitis C virus and its subtypes on the clinical course of liver disease in alcoholics was assessed. Hepatitis C virus infection was confirmed by a reverse transcription and polymerase chain reaction method for the hepatitis C virus NS-5 region in the sera of alcoholics with various stages of histologically proven liver disease. The frequency of hepatitis C virus was significantly higher in alcoholics with chronic hepatitis (73%) than in those with liver fibrosis (18%), alcoholic hepatitis (17%), and fatty liver (0%). Hepatitis C virus subtypes, namely K1 and K2, were determined by dot-blot hybridization analysis of the polymerase chain reaction products with specific probes, and their frequencies were 68% and 32%, respectively. The proportion of patients whose serum transaminase levels returned to normal following 4 weeks of abstinence in hospital was significantly lower in alcoholics with hepatitis C virus viremia (glutamic oxaloacetic transaminase: 53.8%; glutamic pyruvic transaminase: 42.3%) than in those without viremia (glutamic oxaloacetic transaminase: 86.2%, p < 0.01; glutamic pyruvic transaminase: 89.7%, p < 0.01). When alcoholics with the K1 and K2 subtypes of hepatitis C virus were compared, normalization of transaminase levels was less frequent in alcoholics with K1 (glutamic oxaloacetic transaminase: 42.8%; glutamic pyruvic transaminase: 28.6%) than in those with K2 (glutamic oxaloacetic transaminase: 88.9%, p < 0.05; glutamic pyruvic transaminase: 77.8%, P < 0.05). These data indicate that hepatitis C virus infection is associated with a reduced rate of recovery of serum transminase levels following abstinence in subjects with alcoholic liver disease, more so in the K1 subtype than in the K2 subtype.

Alcohol Drinking↗
PubMed1991

Expression of nicotinic acetylcholine receptor subtypes in brain and retina.

Neuronal nicotinic acetylcholine receptors (AChRs) are composed of two types of subunits: ACh-binding (termed alpha 2, alpha 3, alpha 4 ...) and structural (termed beta 2, beta 3, beta 4 ...). AChR subtypes composed of combinations of subunits of these two types encoded by several related genes are expressed in different parts of the nervous system, where they presumably serve different functional roles. Here we identify the ACh-binding subunit of the most prominent chicken brain AChR subtype by N-terminal amino acid sequence and show that it corresponds to the alpha 4 gene. Previously we identified the structural subunit for this AChR subtype from chicken brain as beta 2 by N-terminal amino acid sequence. Thus, this identifies both genes which encode subunits of the major nicotinic AChR subtype in avian brains. By immunoprecipitation, immunohistochemistry, and northern blot analysis we show that alpha 3 (or a very closely related sequence) is expressed at low levels in the brain and relatively high levels in the retina, while alpha 4 is expressed at high levels in the brain and lower levels in the retina. This differential expression indicates that alpha 3-containing 'ganglionic-type' AChRs may be an important AChR subtype in avian retina.

Amino Acid Sequence↗
PubMedDate not supplied

Color image analysis in neuroanatomical research: application to senile plaque subtype quantification in Alzheimer's disease.

Many problems in neuroanatomy and neuropathology require the collection of large data sets and would benefit from a method that allows for rapid quantitative analysis to be carried out on a routine basis. An example is the quantification and subtype classification of the number of senile plaques in post-mortem Alzheimer's disease tissue. A method to reliably automate the analysis of plaques and their underlying subtypes would allow more rigorous and quantitative correlations to be investigated. Computer assisted image analysis of data typically utilizes gray scale images. These methods, however, are only applicable to quantification of objects labeled with a single marker. We sought to extend this type of analysis to double-labeled tissue sections so we could quantify dual labels separately based on their peroxidase color characteristics, analyze the resultant occurrence of overlap between the two labels, and classify senile plaques into discrete subtypes. We present a method for semi-automated color image analysis which allows one to identify separate labels based on histogram mapping of hue, saturation and value as well as apply overlapping feature detection algorithms. The technique is application driven, so that a trained observer can set threshold or object criteria and verify the desired results. These methods were able to yield total "amyloid load" and "dystrophic neurite load" values, generate plaque histograms based on total size, and subtype plaques into diffuse/primitive and neuritic/classical categories. By adjusting feature criteria, we were able to achieve promising agreement (Fisher's R to Z correlation of 0.94) between a human observer and the computer algorithm in the classification of plaque subtypes using three AD cases.

Algorithms↗
PubMed1986

DNA restriction fragment length polymorphisms characteristic for Dw subtypes of DR2.

DNA restriction fragment length polymorphisms (RFLP) can be easily demonstrated in DNA of cells expressing different DR specificities when class II cDNA probes are used for hybridization. Previous studies of DR4+ homozygous typing cells (HTCs) carrying different Dw subtypes, however, detected no RFLP correlating with subtypes. In contrast, we report here Southern blotting studies of DR2+ HTCs carrying different subtypes which showed RFLP patterns characteristic for each subtype, using both DR beta and DQ beta probes and several restriction enzymes. The RFLP between subtypes of DR2 was, however, appreciably lower than that found between DR specificities.

DNA↗
PubMed1986

Identification of new B27 subtypes (B27C and B27D) prevalent in oriental populations.

With the aid of alloreactive cytotoxic T lymphocytes, three subtypes of HLA-B27 can be defined: B27W, B27K, and B27C (non-B27W and non-B27K). The B27C subtype can be distinguished by 1D-IEF, is not recognized by B27W- or B27K-restricted influenza-A-specific cytotoxic T lymphocytes, and is prevalent in Oriental populations. Preliminary data indicate that the various B27 subtypes (W, K, C) are in different linkage disequilibria with HLA-C antigens. A fourth subtype of B27 (non-B27W and non-B27K), designated as B27D, was detected by 1D-IEF. (See accompanying paper by Neefjes et al.) The finding of four B27 subtypes indicates that the serologically defined B27 antigen comprises a family of various, strongly cross-reactive class-I molecules.

Asian People↗
PubMed1990

Full-length DQ beta cDNA sequences of HLA-DR2/DQw1 subtypes: genetic interactions between two DQ beta loci generate human class II HLA diversity.

Two-dimensional gel electrophoresis of DQ molecules from three different Dw subtypes (Dw2, Dw12, and Dw21/FJO) of the HLA-DR2/DQw1 haplotype reveals that one alpha beta heterodimer of DQ molecule is expressed by each subtype and the DQ beta chain is electrophoretically variable among the three DR2/DQw1 subtypes. We have constructed cDNA libraries from the same homozygous typing cells used in the two-dimensional polyacrylamide gel electrophoresis analyses (HTC VYT for Dw2, HTC DHO for Dw12, and HTC FJO for Dw21/FJO) and isolated DQ beta cDNA clones with full-length coding sequences for each subtype. The deduced amino acid sequences show that the DQ beta chains of these three DR2/DQw1 subtypes are highly polymorphic and confirm their electrophoretic heterogeneity: for a mature protein of 229 amino acids, they differ with each other by 10-17 amino acids in the first domain and by 3-7 residues in the C-terminal sequence. Comparison among the available DQ beta sequences representing the four major DQ specificities (DQw1, DQw2, DQw3, and DQw4) in the DQ subregion as defined by serologic method suggests that (1) DR2,Dw2,DQw1 and DR3,DQw2 haplotypes probably interact with each other to generate the DQw3 and DQw4 beta alleles and (2) an evolutionary scheme may be proposed to relate the various beta alleles of the four major DQ specificities.

Alleles↗