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D D Miller

Publications and source records attributed to D D Miller.

At least 37 records · Page 2Linked to original sources
PubMed2000

Synthesis and calpain inhibitory activity of alpha-ketoamides with 2,3-methanoleucine stereoisomers at the P2 position.

A series of novel ketoamides incorporating all four 2,3-methanoleucine stereoisomers at the P2 position was synthesized. The compounds displayed a wide variation in Ki values for inhibition of calpain I depending on the configuration of the P2 methanoleucine residue. However, similar variation in cathepsin B inhibition was not observed suggesting that the S2 pocket of calpain I is more stereosensitive than that of cathepsin B.

Amides↗
PubMed2000

Yohimbine dimers exhibiting binding selectivities for human alpha2a- versus alpha2b-adrenergic receptors.

A series of yohimbine dimers was prepared and evaluated at the human alpha2a- and alpha2b-adrenergic receptors (ARs) expressed in Chinese hamster ovary (CHO) cells. All dimers display higher binding selectivities for alpha2a versus alpha2b subtype than yohimbine, and four compounds (3d, 3e, 3g and 3i) represent the most potent and alpha2a versus alpha2b-AR selective ligands identified so far.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed2000

Biochemical and functional characterization of 1-benzyl substituted trimetoquinol affinity analogs on rat and human beta-adrenoceptors.

The site of interaction for the 1-(3',4',5'-trimethoxybenzyl) group of trimetoquinol (TMQ) with beta-adrenoceptors (beta-ARs) is important for the rational design of highly potent and beta3-AR-selective analogs. 1-Benzyl ring-substituted TMQ analogs were evaluated for binding affinities and biochemical activities (cyclic AMP accumulations) in Chinese hamster ovary (CHO) cells expressing the rat and human beta3-AR, and for functional activities on isolated rat tissues. Binding affinities (K1 approximately 0.055 to 1.5 microM) for the rat beta3-AR and potencies for adenylyl cyclase activation (K(act) approximately 0.43 to 2;5 nM) of the 3'-monoiodo or 3',5'-diiodo derivatives with 4'-isothiocyanato-, 4'-amino, 4'-acetamido, or 4'-alpha-haloacetamido substitutions were higher than those of (-)-isoproterenol, and comparable to those of BRL 37344 [(+/-)-(R*,R*-[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]ph enoxy]-acetic acid sodium]. A similar rank order of binding affinities (K(i) approximately 0.11 to 2.5 microM) and potencies (K(act) approximately 0.45 to 9.5 nM) was obtained for TMQ analogs on the human beta3-AR. The 4'-acetamido and 4'-alpha-chloroacetamido analogs of 3',5'-diiodoTMQ were more potent than (-)-isoproterenol in rat atria (beta1-AR) and rat trachea (beta2-AR) and exhibited partial agonist activities, whereas full agonist activities were observed in rat esophageal smooth muscle (EC50 approximately 2-8 nM, beta3-AR). 4'-alpha-Chloroacetamido-3',5'-diiodoTMQ-mediated chronotropic responses in atria were sustained and resistant to washout. Further, the 4'-alpha-chloroacetamido and 4'-alpha-bromoacetamido analogs of 3',5'-diiodoTMQ demonstrated significant concentration-dependent irreversible binding to the rat beta3-AR. Reversible beta-AR agonists such as (-)-isoproterenol, BRL 37344, and 4'-acetamido-3',5'-diiodoTMQ or nucleophilic 1-amino acids (lysine, glutathione, cysteine) did not protect against this irreversible binding. Thus, the lipophilic 1-benzyl ring of TMQ analogs interacts with a hydrophobic region of the beta-AR that may represent an exo-site or an allosteric binding site.

Adrenergic beta-Agonists↗
PubMed2000

Chiral nonsteroidal affinity ligands for the androgen receptor. 1. Bicalutamide analogues bearing electrophilic groups in the B aromatic ring.

A series of chiral analogues of bicalutamide bearing electrophilic groups (isothiocyanate, N-chloroacetyl, and N-bromoacetyl) on aromatic ring B of the parent molecule were synthesized. These compounds were designed as affinity ligands for the androgen receptor (AR). We prepared the (R)- and (S)-optical isomers of these compounds as pure enantiomers. The AR binding affinities of these compounds were measured in a competitive binding assay with the radiolabeled high-affinity AR ligand, [(3)H]mibolerone. In accordance with our previous results for the enantiomers of bicalutamide, we found that all (R)-isomers demonstrated much higher binding affinity to the AR as compared to their corresponding (S)-isomers. The para-substituted affinity ligands in ring B bound the AR with higher affinities than the corresponding meta-substituted analogues. Oxidation of thioester affinity ligands to their sulfonyl analogues for the para-substituted compounds decreased AR binding affinities and similar modification increased binding affinities for corresponding meta-analogues. The least potent para-substituted sulfonyl compounds had higher AR binding affinities than the most potent meta-substituted sulfonyl compounds. Overall, the para-substituted unoxidized molecules demonstrated the highest AR binding affinity. Subsequent research using AR exchange assays and Scatchard analyses showed that the isothiocyanate affinity ligands (R)-7, (R)-9, and (R)-10 reported herein are the first specific chemoaffinity ligands for the AR.

Androgen Antagonists↗
PubMed2000

Synthesis and human beta-adrenoceptor activity of 1-(3,5-diiodo-4- methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ol derivatives in vitro.

Trimetoquinol (1, TMQ) is a potent nonselective beta-adrenergic receptor (AR) agonist and a thromboxane A(2)/prostaglandin endoperoxide (TP) receptor antagonist, while 3',5'-diiodo-TMQ (2) exhibits beta(3)-AR selectivity. In search of selective beta(3)-AR agonists as potential drugs for the treatment of human obesity and type II diabetes mellitus, a series of 1-(3, 5-diiodo-4-methoxybenzyl)-1,2,3,4-tetrahydroisoquinolin-6-ols has been prepared and evaluated for their biological activities at human beta(1)-, beta(2)-, and beta(3)-ARs expressed in Chinese hamster ovary (CHO) cells. The compounds have been synthesized by the Bischler-Napieralski cyclization of corresponding amides followed by NaBH(4) reduction, and the halogens in the aromatic ring A were introduced by direct halogenation of protected compound 11. Whereas halogen substitution in ring A reduced either potency or intrinsic activity on beta(3)-AR, the non-halogen-substituted compounds 8 and 10 were potent, selective, nearly full agonists for beta(3)-AR.

Adrenergic beta-Agonists↗
PubMed2000

Unprecedented crystallization and X-ray crystal structure of racemic N(alpha)-(t-butyloxycarbonyl)-L-L-phenylalanine N-methoxy-N-methylamide.

Weinreb amide 3 was synthesized using isobutyl chloroformate, carbonyldiimidazole, or ethylcarbodiimide as the coupling agent in the reaction of Boc-phenylalanine with O,N-dimethylhydroxylamine hydrochloride. An optically active oil was isolated along with an optically inactive solid irrespective of the type of coupling agent used. Single crystal X-ray analysis of the solid revealed that it is a racemate. The molecular packing of the crystals reflect the stability of the racemate as opposed to an enantiomerically pure solid.

Calpain↗
PubMed2000

Lipochito-oligosaccharide nodulation factors stimulate cytoplasmic polarity with longitudinal endoplasmic reticulum and vesicles at the tip in vetch root hairs.

Vetch root hair development has four stages: bulge, growing, growth terminating, and full-grown hair. In the assay we used, the nodulation factor induced swellings and outgrowths in growth-terminating hairs. Bulges, swellings, and full-grown hairs have transverse endoplasmic reticulum (ER) and no tip-accumulated vesicles. Growing hairs and outgrowths show vesicle accumulation in the tip and longitudinal subapical ER. Bulge walls and walls of swellings appear mottled.

Antigens, Bacterial↗
PubMed2000

Bidirectional allosteric effects of agonists and GTP at alpha(2A/D)-adrenoceptors.

Agonists and GTP exert reciprocal effects on the stability of the G protein-coupled receptor/G protein complex, implying bidirectional control over the receptor/G protein interface. To investigate this relationship, we compared the ability of a series of hydroxyl-substituted phenethylamine and imidazoline agonists to stimulate [(35)S]guanosine 5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding in membranes from alpha(2A/D)-adrenergic receptor-transfected PC12 cells with the magnitude of the GTP-induced reduction in agonist affinity in [(3)H]rauwolscine-binding studies. Agents previously described as full and partial agonists in functional studies showed similar relative efficacies in promoting GTP binding (r = 0.97) as well as similar relative potencies (r = 0.94). Efficacy among agonists for promotion of [(35)S]GTPgammaS binding was closely correlated with the relative influence of GTPgammaS on agonist binding (r = 0.97), consistent with a bidirectional allosteric influence by agonists and GTP on receptor/G protein complexation. In an additional series of tolazoline derivatives, a range in efficacy from full agonism to strong inverse agonism was observed, depending on the presence or absence of hydroxyl substituents. Together these results suggest that agonist-induced repositioning of transmembrane helices via their hydroxyl interactions is a critical determinant of the stability of the receptor/G protein complex and therefore of agonist efficacy.

Adrenergic Agonists↗
PubMed2000

Defining quality health care with outcomes assessment while achieving economic value.

The effectiveness of a procedure is increasingly guided by the evaluation of patient outcomes. Outcomes data is used to develop clinical pathways of care and to define appropriate resource-use levels without sacrificing quality of care. Integration of the economic implications of medical services into an outcome-based guideline allows for the development of disease-management strategies. In cardiovascular medicine, risk reduction is associated with high cost due to the "pay-back" of new technologies and therapies. A major challenge is to define a balance between "high tech" care and cost. This paper devises an outpatient evidence-based guideline using clinical and economic outcomes data for the diagnosis of coronary disease.

Cardiovascular Diseases↗
PubMed2000

Review and management of clozapine side effects.

Clozapine has demonstrated superior efficacy in relieving positive and negative symptoms in treatment-resistant schizophrenic patients; unlike other antipsychotics, it causes minimal extrapyramidal side effects (EPS) and has little effect on serum prolactin. Despite these benefits, the use of clozapine has been limited because of infrequent but serious side effects, the most notable being agranulocytosis. In recent years, however, mandatory blood monitoring has significantly reduced both the incidence of agranulocytosis and its associated mortality. The occurrence of seizures appears to be dose-related and can generally be managed by reduction in clozapine dosage. Less serious and more common side effects of clozapine including sedation, hypersalivation, tachycardia, hypotension, hypertension, weight gain, constipation, urinary incontinence, and fever can often be managed medically and are generally tolerated by the patient. Appropriate management of clozapine side effects facilitates a maximization of the benefits of clozapine treatment, and physicians and patients alike should be aware that there is a range of benefits to clozapine use that is wider than its risks.

Agranulocytosis↗
PubMed2000

Asymmetric synthesis of 2,3-methanoleucine stereoisomers from common intermediates.

2,3-Methanoamino acids are useful probes for studying the bioactive conformation of peptides and for investigating the effect of local conformational constraints on the activity of peptidomimetics. We synthesized all four stereoisomers of Cbz-protected 2, 3-methanoleucine for incorporation into peptidomimetic inhibitors of calpain. While the synthesis of 2,3-methanoamino acids has been previously reported, our procedure offers a versatile route in which the pair of diastereomers of each geometric isomer was synthesized from a common intermediate.

Amino Acids↗
PubMed2000

Clinical and economic outcomes assessment in nuclear cardiology.

The future of nuclear medicine procedures, as understood within our current economic climate, depends upon its ability to provide relevant clinical information at similar or lower comparative costs. With an ever-increasing emphasis on cost containment, outcome assessment forms the basis of preserving the quality of patient care. Today, outcomes assessment encompasses a wide array of subjects including clinical, economic, and humanistic (i.e., quality of life) outcomes. For nuclear cardiology, evidence-based medicine would require a threshold level of evidence in order to justify the added cost of any test in a patient's work-up. This evidence would include large multicenter, observational series as well as randomized trial data in sufficiently large and diverse patient populations. The new movement in evidence-based medicine is also being applied to the introduction of new technologies, in particular when comparative modalities exist. In the past 5 years, we have seen a dramatic shift in the quality of outcomes data published in nuclear cardiology. This includes the use of statistically rigorous risk-adjusted techniques as well as large populations (i.e., > 500 patients) representing multiple diverse medical care settings. This has been the direct result of the development of multiple outcomes databases that have now amassed thousands of patients worth of data. One of the benefits of examining outcomes in large patient datasets is the ability to assess individual endpoints (e.g., cardiac death) as compared with smaller datasets that often assess combined endpoints (e.g., death, myocardial infarction, or unstable angina). New technologies for the diagnosis of coronary artery disease have contributed to the rising costs of care. In the United States and in Europe, costs of care have risen dramatically, consuming an ever-increasing amount of available resources. The overuse of diagnostic angiography often leads to unnecessary revascularization that does not lead to improvement in outcome. Thus, the potential exists that stress SPECT imaging, a highly effective diagnostic tool, could effect substantial change in reducing inappropriate use of an invasive procedure resulting in cost effective cardiac care. A synthesis of current economic evidence in gated SPECT imaging will be presented. In conclusion, a current state of the evidence review is presented on the clinical and economic data using nuclear cardiology imaging.

Angiography↗
PubMed1999

Affinity labeling of the androgen receptor with nonsteroidal chemoaffinity ligands.

We synthesized a series of potential chemoaffinity ligands for the androgen receptor (AR) by means of structural modifications of bicalutamide, a known nonsteroidal antiandrogen used in the treatment of hormone-dependent prostate cancer. We determined AR binding affinities of these ligands, identified chemoaffinity ligands by exchange assays, and confirmed irreversible binding to the AR by Scatchard analyses. AR binding affinity was determined in a competitive binding assay with a radiolabeled high-affinity AR ligand, [3H]mibolerone ([3H]MIB). For exchange assays, AR were incubated with an excess of each ligand, and then adsorbed onto hydroxyapatite (HAP). HAP-bound AR then were incubated with [3H]MIB to determine the remaining exchangeable specific binding sites. To determine the concentration of binding sites (Bmax), using Scatchard analysis, AR were incubated with a fixed concentration of ligand and increasing [3H]MIB concentrations. The ligands showed a wide range of AR binding affinities. In the exchange assays, three isothiocyanate derivatives of R-bicalutamide, the p-isothiocyanate (R-4), the p-thio-isothiocyanate (R-6), and the m-isothiocyanate (R-3), reduced exchangeable specific binding of [3H]MIB by 85, 84, and 50%, respectively. The S-isomer of p-thio-isothiocyanate (S-6), which showed 700-fold lower AR binding affinity than R-6, did not reduce exchangeable specific binding of [3H]MIB. In Scatchard analyses, the isothiocyanate derivatives R-3, R-4, and R-6 showed significant and progressive reduction in Bmax at increasing concentrations. The results indicate that initial specific reversible AR binding was required for subsequent covalent labeling, and that R-3, R-4, and R-6 bound the AR specifically and irreversibly. These isothiocyanate derivatives of R-bicalutamide are the first specific chemoaffinity ligands for the AR, and will provide valuable tools for the molecular characterization of the ligand binding domain of the AR.

Affinity Labels↗
PubMed1999

Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms.

All research on schizophrenia depends on selecting the correct phenotype to define the sample to be studied. Definition of the phenotype is complicated by the fact that there are no objective markers for the disorder. Further, the symptoms are diverse, leading some to propose that the disorder is heterogeneous and not a single disorder or syndrome. This article explores an alternative possibility. It proposes that schizophrenia may be a single disorder linked by a common pathophysiology (a neurodevelopmental mechanism), which leads to a misconnection syndrome of neural circuitry. Evidence for disruption in a specific circuit is explored: the cortical-thalamic-cerebellar-cortical circuit (CCTCC). It is suggested that a disruption in this circuit leads to an impairment in synchrony, or the smooth coordination of mental processes. When synchrony is impaired, the patient suffers from a cognitive dysmetria, and the impairment in this basic cognitive process defines the phenotype of schizophrenia and produces its diversity of symptoms.

Brain Mapping↗
PubMed1999

Are presenilins intramembrane-cleaving proteases? Implications for the molecular mechanism of Alzheimer's disease.

The amyloid-beta protein (Abeta) is strongly implicated in the pathogenesis of Alzheimer's disease. The final step in the production of Abeta from the amyloid precursor protein (APP) is proteolysis by the unidentified gamma-secretases. This cleavage event is unusual in that it apparently occurs within the transmembrane region of the substrate. Studies with substrate-based inhibitors together with molecular modeling and mutagenesis of the gamma-secretase cleavage site of APP suggest that gamma-secretases are aspartyl proteases that catalyze a novel intramembranous proteolysis. This proteolysis requires the presenilins, proteins with eight transmembrane domains that are mutated in most cases of autosomal dominant familial Alzheimer's disease. Two conserved transmembrane aspartates in presenilins are essential for gamma-secretase activity, suggesting that presenilins themselves are gamma-secretases. Moreover, presenilins also mediate the apparently intramembranous cleavage of the Notch receptor, an event critical for Notch signaling and embryonic development. Thus, if presenilins are gamma-secretases, then they are also likely the proteases that cleave Notch within its transmembrane domain. Another protease, S2P, involved in the processing of the sterol regulatory element binding protein, is also a multipass integral membrane protein which cleaves within or very close to the transmembrane region of its substrate. Thus, presenilins and S2P appear to be members of a new type of polytopic protease with an intramembranous active site.

Alzheimer Disease↗
PubMed1999

2-Amino-4-benzyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridines: novel selective beta3-adrenoceptor agonists.

Trimetoquinol (TMQ, 7) is a potent nonselective beta-adrenoceptor (AR) agonist. Replacement of the catechol moiety of TMQ with a 2-aminothiazole group resulted in novel thiazolopyridine derivatives 9-11 which have been synthesized and evaluated for biological activity on human beta1-, beta2-, and beta3-AR. The Bischler-Napieralski reaction has been employed as a novel approach to construct the 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring system. Although in radioligand binding studies analogues 9 and 10 did not show selectivity toward beta3-AR, they exhibited a high degree of selective beta3-AR agonist activity in functional assays. Moreover, the beta3-AR agonist activity of the 2-aminothiazole derivatives is abolished by N-acetylation (analogue 11) or ring opening (analogue 25). This illustrates the importance of the intact 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine ring for beta3-AR activity.

Adrenergic beta-Agonists↗
PubMed1999

Depolarization of membrane potential and the smooth muscle contraction by isothiocyanatobenzyl imidazoline in guinea-pig stomach circular muscle.

Isothiocyanatobenzyl imidazoline (IBI) produces characteristic slowly developing contraction of many smooth muscle preparations including the circular smooth muscle of the guinea-pig stomach. Changes in the membrane potential were recorded intracellularly, and the muscle contraction induced by IBI was investigated. IBI at 100 micromol/l slowly produced a sustained depolarization of the membrane with a maximum change of approximately 15 mV. This depolarization could not be blocked by 1-hyoscyamine, 100 nmol/l. An imidazoline analogue, oxymetazoline at 1 micromol/l, did not change the resting membrane potential as observed after IBI. Significant membrane depolarization after IBI still occurred in Ca2+-free medium. During IBI-induced depolarization, sudden reduction of Na+ to 30 mmol/l in the medium reduced the depolarization slightly. IBI-induced depolarization was additive with that produced by 20 mmol/l K+ in the medium. In the presence of tetraethylammonium chloride or levcromakalim or nifedipine, IBI continued to depolarize the membrane although functional pharmacological experiments showed that the contractile effects of IBI were significantly inhibited by 30 micromol/l levcromakalim and abolished by 100 nmol/l nifedipine. At 100 micromol/l phentolamine (reported by others as an inhibitor of ATP-sensitive potassium channels) completely blocked IBI-induced contraction. Phentolamine (30 micromol/l) blocked the contractile effects of IBI by 50%. On the other hand, S(-)-Bay K 8644, a voltage-dependent calcium channel activator, was additive with the contractile response of IBI. These results indicated that IBI produced membrane depolarization and contraction of the guinea-pig stomach circular muscle, by a mechanism not involving muscarinic receptors or alpha-adrenoceptors. Even though levcromakalim, an ATP-sensitive potassium channel opener, could not inhibit IBI-induced depolarization, the ATP-sensitive potassium channel and the voltage-dependent calcium channel may be intrinsically linked with the action of IBI.

Animals↗