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E Richelson

Publications and source records attributed to E Richelson.

At least 55 records · Page 3Linked to original sources
PubMed1997

Pharmacokinetic drug interactions of new antidepressants: a review of the effects on the metabolism of other drugs.

Seven of the newest antidepressants are the serotonin-selective reuptake inhibitors (fluoxetine, sertraline, paroxetine, and fluvoxamine [currently approved in the United States only for obsessive-compulsive disorder]), a serotonin-norepinephrine reuptake inhibitor (venlafaxine), a postsynaptic serotonin antagonist-presynaptic serotonin reuptake inhibitor (nefazodone), and a presynaptic-postsynaptic noradrenergic-serotonergic receptor antagonist (mirtazapine). Many of these drugs are potent inhibitors of the cytochrome P-450 enzymes (CYPs) of the liver. The isoforms of the CYPs most relevant to the use of antidepressants are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. CYP inhibition may affect the metabolism of numerous drugs in several classes that are substrates for these isoenzymes, with potentially serious consequences. To minimize the potential for an adverse event, the practitioner must remember the drug-drug interactions, and possible consequences when one of these antidepressants is being prescribed. A "primer" on drug metabolism is included herein, which serves as a basis for understanding these interactions., Each of the isoenzymes of the CYPs is discussed in relationship to the drugs they metabolize, and appropriate cautions are recommended for concurrent administration of these new antidepressants and other drugs most frequently prescribed to elderly patients.

1-Naphthylamine↗
PubMed1996

Proposed ligand binding site of the transmembrane receptor for neurotensin(8-13).

We report here the first proposed ligand binding site of the transmembrane receptor for neurotensin(8-13) in human and rat, the corresponding bound conformation of the peptide ligand, and site-directed mutagenesis studies that support the binding site model. These three-dimensional structures were generated by using a heuristic approach in conjunction with experimental data. The proposed neurotensin(8-13) binding site is primarily composed of eight residues (i.e., Phe326, Ile329, Trp334, Phe337, Tyr339, Phe341, Tyr342, and Tyr344 in the human receptor; Phe331, Ile334, Trp339, Phe342, Phe344, Phe346, Tyr347, and Tyr349 in the rat receptor) located in the third extracellular loop. The seven aromatic residues form an aromatic pocket on the extracellular surface of the neurotensin receptor to accommodate its ligands apparently by cation-pi, pi-pi, and hydrogen bonding interactions. The neurotensin(8-13) ligand adopts a compact conformation at the proposed binding site. In the bound conformation of neurotensin(8-13), the backbone of Arg9-Pro10-Tyr11-Ile12 forms the proline type I turn, and the hydroxy group of Tyr11 interacts with the two guanidinium groups of Arg8 and Arg9. These guanidinium groups are curled toward the hydroxy group so that they interact electrostatically with the hydroxy group, and that the guanidinium group of Arg9 forms an intra-hydrogen bond with the hydroxy group. The proposed three-dimensional structure may not only provide a basis for rationalizing mutations of the neurotensin receptor gene but also offer insights into understanding the binding of many neurotensin analogs, biological functions of the neurotensin receptors, and structural elements for species specificity of the neurotensin receptors, and may expedite developing nonpeptidic neurotensin mimetics for the potential treatment of the neuropsychiatric diseases.

Amino Acid Sequence↗
PubMed1996

Chimeric rat/human neurotensin receptors localize a region of the receptor sensitive to binding of a novel, species-specific, picomolar affinity peptide.

Recently, we reported the development of a species-specific neurotensin analog that displays selective binding affinity at the rat and human neurotensin (NT) receptor, L-[3,2'-Nal11]NT(8-13) (where Nal is naphthylalanine) (NT19). We have developed another neurotensin analog, L-[3,1'-Nal11]NT(8-13), (NT34), that exhibits a 126-fold difference in binding affinities between the rat and human receptors. This compound differs from our previous reported species-specific ligand in the steric positioning of the naphthyl ring on the L-alanine side chain. For NT34, the observed Kd values at the rat and human neurotensin receptors were 0.046 and 5.8 nM, respectively. In stimulating phosphatidylinositol turnover, the observed EC50 values were 2.8 nM and 130 nM in rat and human, respectively. We constructed a series of chimeric rat/human neurotensin receptor genes and expressed them by transient transfection into human embryonic kidney (HEK-293) cells. Radioligand binding assays were then performed using neurotensin and NT34. Our results led us to propose a region of the neurotensin receptor that may be involved in determining species specificity, i. e. the transmembrane VI, the third extracellular loop, and transmembrane VII regions of the neurotensin receptor.

Amino Acid Sequence↗
PubMed1996

Sodium nitroprusside-induced apoptotic cellular death via production of hydrogen peroxide in murine neuroblastoma N1E-115 cells.

Sodium nitroprusside is widely used in pharmacological studies as a potent vasodilator or a nitric oxide donor. The mechanisms of cellular death induced by sodium nitroprusside were investigated in murine neuroblastoma N1E-115 cells. Sodium nitroprusside reduced the cellular viability, and the DNA extracted from treated cells showed a ladder-like intranucleosomal fragmentation pattern, which is an indication of apoptosis. The DNA fragmentations were also visualized by in situ nick translation. The cellular death was attenuated by cycloheximide, indicating that ongoing protein synthesis was essential for the initiation of the degenerative response. However, other nitric oxide donors did not decrease the cellular viability. The nitric oxide scavenger, hemoglobin, had no effect on sodium nitroprusside-induced cellular death. Furthermore, sodium cyanide, which is formed by the metabolism of sodium nitroprusside, did not cause cellular death. On the other hand, hydrogen peroxide, another product of sodium nitroprusside metabolism, reduced the cellular viability and induced DNA fragmentation. In addition, the cell damage induced by sodium nitroprusside was enhanced by a medium without fetal bovine serum. In conclusion, we proposed that hydrogen peroxide is the important toxic species for induction of apoptosis in N1E-115 cells exposed to sodium nitroprusside.

Animals↗
PubMed1996

Synaptic effects of antidepressants.

Catecholamines, especially norepinephrine (NE) and serotonin (5-hydroxytryptamine [5-HT]), have been implicated in the pathophysiology of depression. However, their exact roles and their interrelationship are not completely understood. Antidepressants have various effects on the body, including action at the neuronal synapses of the brain; the two most important of these effects are blockade of the reuptake of neurotransmitters, including NE, 5-HT, and dopamine, and blockade of certain neurotransmitter receptors. Currently available antidepressants may be classified as inhibitors of monoamine oxidase or as blockers of biogenic amine neurotransmitter reuptake, the latter best describing tricyclic antidepressants and selective 5-HT-reuptake inhibitors, because they block the reuptake of one or more neurotransmitters. However, recently introduced antidepressants, such as the 5-HT-NE-reuptake inhibitors, have synaptic effects that differ from those of older compounds. These synaptic effects are important in explaining certain side effects and drug-drug interactions associated with all classes of antidepresants. This article reviews the synaptic effects of marketed antidepressant agents to elucidate the anticipated side effects and drug-interaction potential of these agents.

Animals↗
PubMed1996

Preclinical pharmacology of neuroleptics: focus on new generation compounds.

This article reviews the preclinical pharmacology of neuroleptics, with focus on the newer generation compounds: clozapine, risperidone, olanzapine, sertindole, and quetiapine. All of these newer compounds are considered to be atypical neuroleptics, based on certain criteria, which are reviewed. Several hypotheses about the molecular mechanisms that explain atypicality are considered. Finally, the in vitro receptor binding data presented for these and some older compounds are related to the therapeutic and adverse effects of these drugs.

Antipsychotic Agents↗
PubMed1996

A method to estimate in vivo D2 receptor occupancy by antipsychotic drugs.

A computational method is presented to estimate in vivo receptor occupancies of frequently used antipsychotic medications, which may provide a way to determine their central nervous system (CNS) effects in humans. The method can be used to estimate occupancies of several receptor types based on the daily dose of antipsychotic medication. Estimates of D2 receptor occupancy by haloperidol based on this equation were compared with those yielded by positron emission tomography (PET) measures in humans for the same compounds and dosages: the results of this comparison validated the approach.

Antipsychotic Agents↗
PubMed1995

Pharmacological and biochemical profiles of unique neurotensin 8-13 analogs exhibiting species selectivity, stereoselectivity, and superagonism.

Recently, the rat neurotensin receptor and the two human neurotensin receptor clones (differing by one amino acid residue) have been isolated. We present results with 33 newly synthesized neurotensin analogs. We have evaluated their binding potency at the three neurotensin receptor clones by determining equilibrium dissociation constants and coupling to phosphatidylinositol turnover. Our work focused on position 8 and 9 substitutions as well as position 11 of the neurotensin hexamer NT8-13. The results presented include: 1) the development of a compound that is species selective, with a binding potency at the rat receptor that is 20-fold more potent than at the human receptor; 2) the development of a pair of stereoselective compounds with the L-isomer exhibiting 190-700-fold more potency than the D-isomer; and 3) the development of an agonist that has a Kd of 0.3 and 0.2 nM at the human and rat neurotensin receptor, respectively, ranking it as among the most potent tested. Also, we present the first evidence that 1) the effect of pi electrons at position 11 (L-Tyr) are important for binding to the neurotensin receptor, and 2) the length of the side chain on position 9 (L-Arg) changes binding potency.

Amino Acid Sequence↗
PubMed1995

Regulation of neurotensin receptor mRNA expression by the receptor antagonist SR 48692 in the rat midbrain dopaminergic neurons.

In this study, we demonstrated that the tyrosine hydroxylase-like immuno-reactive (possibly dopaminergic) neurons express neurotensin receptor mRNA in the rat substantia nigra and in the ventral tegmental area. Additionally, 2 weeks treatment with the neurotensin receptor antagonist SR 48692 increased mRNA levels in the substantia nigra. These data suggest that neurotensin receptor expression in the perikarya and in the terminal regions of dopaminergic neurons is regulated by its endogenous agonist in vivo.

Animals↗
PubMed1995

Heterogeneity of melanized neurons expressing neurotensin receptor messenger RNA in the substantia nigra and the nucleus paranigralis of control and Parkinson's disease brain.

We have recently cloned the neurotensin receptor from human substantia nigra. Using in situ hybridization techniques, with an 35S-labeled antisense RNA probe complementary to this receptor complementary DNA, we studied the expression of the human neurotensin receptor in the brain from control and Parkinson's disease subjects. We also performed an analogous study with rat brain. Neurotensin receptor messenger RNA was present in high levels in melanized neurons of the substantia nigra pars compacta and the nucleus paranigralis (the ventral tegmental area for rat brain). Background levels of signals for neurotensin receptor messenger RNA were detected in the nucleus ruber, the colliculus inferior and the striatal subdivisions (the nucleus caudatus, the putamen and the nucleus accumbens) of both human and rat brain. All these areas, except the nucleus ruber and the collicus inferior, contain very high to high levels of neurotensin receptor binding sites. Additionally, Parkinson's disease brains had markedly fewer melanized (possibly dopaminergic) neurons, as expected, and correspondingly very low or background levels of messenger RNA for neurotensin receptor. We have also demonstrated heterogeneity among the melanized cells expressing messenger RNA encoding the neurotensin receptor in the substantia nigra and the nucleus paranigralis of human brain. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. In general, the expression of the messenger RNA within the highly and evenly melanized neurons was lower than that found in low or unevenly pigmented neurons. The neurons in the nucleus paranigralis had lower melanin pigmentation and higher expression of neurotensin receptor messenger RNA. The low pigmented neurons in the ventral tier of the substantia nigra had relatively high expression. On the other hand, highly and evenly melanized neurons in these regions of the brain had low expression of neurotensin receptor messenger RNA. Together with the previous binding data, it is suggested that not only in rat brain, but also in human brain, melanized (possibly dopaminergic) neurons in the substantia nigra and the nucleus paranigralis (ventral tegmental area of rat brain) synthesize neurotensin receptors and express them in their perikarya and the terminal regions. Additionally, the heterogeneity of the melanized neurons in human brain may play a role in the normal function of dopaminergic systems and probably in the etiology of some neurological and psychiatric disorders.

Aged↗
PubMed1995

Serum anticholinergic activity in hospitalized older persons with delirium: a preliminary study.

OBJECTIVE: To evaluate the relationship between total serum anticholinergic activity (SAA) and the presence or absence of delirium in older hospitalized persons on general medical wards. DESIGN: Case-control study and within-subjects repeated-measures in recovered delirious patients. SETTING: Minneapolis Veterans Affairs Medical Center medical wards. PARTICIPANTS: Eleven male delirious patients (DSM-III-R criteria) aged 60 or older and 11 comparably aged male nondelirious controls. MEASUREMENTS: Radioreceptor bioassay of total SAA using tritiated quinuclidinyl benzilate (QNB) binding to muscarinic receptors. Results are expressed in terms of atropine equivalents (nM). MAIN RESULTS: Mean SAA was significantly elevated in the delirious group (mean +/- SD = 6.05 +/- 2.97 nM atropine equivalents) compared with the controls (3.38 +/- 2.49; t(20) = 2.28, P < .05). At study entry, mean SAA was significantly higher in delirious subjects whose symptoms eventually resolved completely (mean +/- SD = 7.77 +/- 2.37) compared with subjects whose delirious symptoms persisted (3.99 +/- 2.30; t(9) = 2.68, P < .05). All six patients in whom delirium resolved completely had a decrease in serum anticholinergic activity when measured during delirium (7.77 +/- 2.37) and after symptom resolution (3.92 +/- 2.61; t(5) = 3.29, P < .05). CONCLUSIONS: Our findings suggest that serum anticholinergic activity may play a role in delirium in medical inpatients. The relationships between SAA and delirium in medical patients and between total SAA and medication use warrant further study.

Aged↗
PubMed1995

Regulation of daily rhythm of body temperature by neurotensin receptor in rats.

It is proposed that neurotensin receptor mediated signal transduction may play an important role in the thermoregulatory control in the brain. In this study, a significant increase in body core temperature was observed with SR 48692, a neurotensin receptor antagonist, after treatment of rats at light phase when the temperature is regulated low. On the other hand, SR 48692 delayed the physiological decline of body core temperature at dark phase when the temperature is highly regulated. We also found slight daily rhythmicity, though not significant, in neurotensin/neuromedin N precursor protein mRNA levels in the medial preoptic nucleus using in situ hybridization technique. Our results support the hypothesis that endogenous neurotensin receptor agonists play a physiological role in the central modulation of body core temperature in rats.

Animals↗
PubMed1995

Bupropion: a review of its mechanism of antidepressant activity.

BACKGROUND: The mechanism of action of the novel antidepressant bupropion remains unclear after many years of study. A review of the relevant biochemical, in vivo brain microdialysis, electrophysiologic, behavioral, and clinical data clarifies what is known about this unique compound and suggests possible modes of action. METHOD: A panel of 11 experts was convened for a conference to discuss bupropion's mechanism of antidepressant activity. Four of the panelists presented current research findings, followed by a discussion. RESULTS: (1) Biochemical studies suggest down-regulation of postsynaptic beta-adrenoceptors and desensitization of the norepinephrine-stimulated adenylate cyclase in the rat cortex occur only after chronic administration of very high doses of bupropion. (2) In vivo brain microdialysis studies demonstrate that, after chronic administration, there is an enhancement of bupropion-induced increases in extracellular dopamine in the nucleus accumbens. (3) Electrophysiologic data show that with acute dosing, bupropion reduces the firing rates of noradrenergic neurons in the locus ceruleus. The firing rates of dopaminergic neurons are reduced by bupropion in the A9 and A10 areas of the brain, but only at very high doses, and bupropion does not alter the firing rates of serotonergic neurons in the dorsal raphe. (4) Behavioral studies show that the most active metabolite of bupropion, hydroxybupropion (306U73), appears to be responsible for a large part of the compound's effects in animal models of antidepressant activity. (5) Clinical studies indicate that bupropion enhances noradrenergic functional activity as reflected by an increased excretion of the hydroxy metabolite of melatonin, while at the same time producing a presumably compensatory decrease in norepinephrine turnover. In one study, bupropion elevated plasma levels of the dopamine metabolite homovanillic acid in nonresponders, but not in responders. CONCLUSION: The mechanism of action of bupropion appears to have an unusual, not fully understood, noradrenergic link. The bupropion metabolite hydroxybupropion probably plays a critical role in bupropion's antidepressant activity, which appears to be predominantly associated with long-term noradrenergic effects. The mild central nervous system activating effects of bupropion appear to be due to weak dopaminergic mechanisms. There is some evidence that dopamine may contribute to bupropion's antidepressant properties. Antidepressant effects of bupropion are not serotonergically mediated.

Animals↗
PubMed1995

Pharmacological characterization of SR 48692 sensitive neurotensin receptor in human pancreatic cancer cells, MIA PaCa-2.

Previously, one type of human neurotensin receptor has been molecularly cloned. Recently, it has been proposed that a subtype of neurotensin receptor exists, which is not sensitive to newly synthesized neurotensin receptor antagonist SR 48692. In this study, we characterize the pharmacological properties of neurotensin receptor expressed in human pancreatic cancer cells, MIA PaCa-2. In binding studies with [3H]neurotensin, the data fit a model for a single population of high-affinity binding sites that are competitively antagonized by SR 48692. The rank order of the equilibrium dissociation rate constants for neurotensin(8-13), neurotensin, neuromedin N, [Ala11] neurotensin(8-13), and SR 48692 were similar to those found with the molecularly cloned human neurotensin receptors. Additionally, the intracellular calcium mobilization and the growth of MIA PaCa-2 cells induced by neurotensin receptor agonist were completely inhibited by SR 48692. In conclusion, our results showed that MIA PaCa-2 cells express functional and SR 48692-sensitive-type neurotensin receptors. It is suggested that the neurotensin receptor antagonist SR 48692 may be useful in the treatment of pancreatic cancers that possess this type of neurotensin receptor.

Calcium↗
PubMed1994

Rational design of novel neurotensin mimetics: discovery of a pharmacologically unprecedented agent exhibiting concentration-dependent dual effects as antagonist and full agonist.

We report the rational design of novel neurotensin mimetics through use of the Multiple Template Approach. This approach is based on our notion that a flexible peptide can be replaced by a partially flexible molecule, identified through testing a comparatively small number of molecules possessing a different intrinsic availability of conformations of the native peptide. The Multiple Template Approach has culminated in the discovery of a pharmacologically unprecedented agent, which behaves as a neurotensin antagonist at low concentration and as a full neurotensin agonist at high concentration.

Amino Acid Sequence↗
PubMed1994

Binding of antidepressants to human brain receptors: focus on newer generation compounds.

Using radioligand binding assays and post-mortem normal human brain tissue, we obtained equilibrium dissociation constants (Kds) for 17 antidepressants and two of their metabolites at histamine H1, muscarinic, alpha 1-adrenergic, alpha 2-adrenergic, dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2 receptors. Several newer antidepressants were compared with older drugs. In addition, we studied some antimuscarinic, antiparkinson, antihistamine, and neuroleptic compounds at some of these receptors. For the antidepressants, classical tricyclic antidepressants were the most potent drugs at five of the seven receptors (all but alpha 2-adrenergic and 5-HT1A receptors). The chlorophenylpiperazine derivative antidepressants (etoperidone, nefazodone, trazodone) were the most potent antidepressants at alpha 2-adrenergic and 5-HT1A receptors. Of ten antihistamines tested, none was more potent than doxepin at histamine H1 receptors. At muscarinic receptors antidepressants and antihistamines had a range of potencies, which were mostly weaker than those for antimuscarinics. From the in vitro data, we expect adinazolam, bupropion, fluoxetine, sertraline, tomoxetine, and venlafaxine not to block any of these five receptors in vivo. An antidepressant's potency for blocking a specific receptor is predictive of certain side effects and drug-drug interactions. These studies can provide guidelines for the clinician in the choice of antidepressant.

Antidepressive Agents↗