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Biomedical subjects

R B Rothman

Publications and source records attributed to R B Rothman.

At least 37 records · Page 2Linked to original sources
PubMed2001

In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats.

Ibogaine is a naturally occurring compound with purported antiaddictive properties. When administered to primates, ibogaine is rapidly o-demethylated to form the metabolite 12-hydroxyibogamine (noribogaine). Peak blood levels of noribogaine exceed those of ibogaine, and noribogaine persists in the bloodstream for at least 1 day. Very few studies have systematically evaluated the neurobiological effects of noribogaine in vivo. In the present series of experiments, we compared the effects of i.v. administration of ibogaine and noribogaine (1 and 10 mg/kg) on motor behaviors, stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. Ibogaine caused dose-related increases in tremors, whereas noribogaine did not. Both ibogaine and noribogaine produced significant elevations in plasma corticosterone and prolactin, but ibogaine was a more potent stimulator of corticosterone secretion. Neither drug altered extracellular DA levels in the nucleus accumbens. However, both drugs increased extracellular 5-HT levels, and noribogaine was more potent in this respect. Results from in vitro experiments indicated that ibogaine and noribogaine interact with 5-HT transporters to inhibit 5-HT uptake. The present findings demonstrate that noribogaine is biologically active and undoubtedly contributes to the in vivo pharmacological profile of ibogaine in rats. Noribogaine is approximately 10 times more potent than ibogaine as an indirect 5-HT agonist. More importantly, noribogaine appears less apt to produce the adverse effects associated with ibogaine, indicating the metabolite may be a safer alternative for medication development.

Animals↗
PubMed2000

Synthesis and transporter binding properties of bridged piperazine analogues of 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR 12909).

A series of analogues related to 1-[2-(diphenylmethoxy)ethyl]-4-(3-phenylpropyl)piperazine (2) and 1-¿2-[bis(4-fluorophenyl)methoxy]ethyl¿-4-(3-phenylpropyl)piperazine (3) (GBR 12935 and GBR 12909, respectively), in which the piperazine moiety was replaced by bridged piperazines for structural rigidity, has been designed, synthesized, and evaluated for their ability to bind to the dopamine transporter (DAT) and to inhibit the uptake of (3)H-labeled dopamine (DA). The binding data indicated that compounds 7 and 11, the N-methyl- and N-propylphenyl-3,8-diaza[3.2. 1]bicyclooctane analogues of 3, showed high affinity for the DAT (IC(50) = 8.0 and 8.2 nM, respectively), and 7 had high selectivity at the DAT relative to the serotonin transporter (SERT) (88- and 93-fold for binding and reuptake, respectively). They also displayed linear activity in DA uptake inhibition, possessing a similar binding and reuptake inhibition profile to 3. The N-indolylmethyl analogue 16 showed the highest affinity (IC(50) = 1.4 nM) of the series, with a 6-fold increase over its corresponding N-phenypropyl derivative 11. Interestingly, this compound exhibited a high ratio (29-fold) of IC(50) for the inhibition of DA reuptake versus binding to the DAT. Replacing the piperazine moiety of 2 and 3 with (1S, 4S)-2,5-diazabicyclo[2.2.1]heptane resulted in compounds 23-26, which showed moderate to poor affinity (IC(50) = 127-1170 nM) for the DAT. Substitution of the homopiperazine moiety of 4 with a more rigid 3,9-diazabicyclo[4.2.1]nonane gave compounds 28-33. However, the binding data showed that compound 32 displayed a 10-fold decrease in affinity at the DAT and a 100-fold decrease in selectivity at the DAT relative to the SERT compared to its corresponding homopiperazine compound 4.

Animals↗
PubMed2000

Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline.

A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline affected its affinity and selectivity greatly. Except for the 4-methoxy derivative 13a,which had the same high affinity at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues (13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites. However, some of the analogues were more selective than indatraline, and the 6-methoxy derivative 13c displayed the highest affinity for both the serotonin and norepinephrine transporters. This compound retained reasonable affinity for the dopamine transporter and is a promising template for the development of a long-acting inhibitor of monoamine transporters. Such inhibitors have potential as medications for treatment, as a substitution medication, or for prevention of the abuse of methamphetamine-like stimulants.

Animals↗
PubMed2000

Evidence for possible involvement of 5-HT(2B) receptors in the cardiac valvulopathy associated with fenfluramine and other serotonergic medications.

BACKGROUND: Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis. METHODS AND RESULTS: Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (+/-)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (+/-)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (+/-)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT(2B) receptor and were partial to full agonists at the 5-HT(2B) receptor. CONCLUSIONS: Our data imply that activation of 5-HT(2B) receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT(2B) receptors are unlikely to produce VHD. We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT(2B) receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT(2B) receptors.

Dose-Response Relationship, Drug↗
PubMed2000

Probes for narcotic receptor-mediated phenomena. 27. Synthesis and pharmacological evaluation of selective delta-opioid receptor agonists from 4-[(alphaR)-alpha-(2S,5R)-4-substituted-2, 5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamides and their enantiomers.

Potent, selective, and efficacious delta-opioid receptor agonists such as (+)-4-[(alphaR)-alpha-(2S,5R)-4-allyl-2, 5-dimethyl-1-piperazinyl-3-methoxybenzyl]-N,N-diethylbenzamide [SNC80, (+)-2] have been found to be useful tools for exploring the structural requirements which are necessary for ligands which interact with the delta-receptor. To determine the necessity for the 4-allyl moiety in (+)-2, this substituent was replaced with a variety of 4-alkyl, 4-arylalkyl, and 4-alkenyl substituents. The corresponding enantiomers of these compounds were also synthesized. The binding affinities for the mu-, delta-, and kappa-opioid receptors and efficacies in the functional GTPgammaS binding assay were determined for the (+)-2 related compounds and their enantiomers. The 4-crotyl analogue was found to have similar delta-receptor affinity and efficacy as (+)-2, but the 4-cyclopropylmethyl analogue, in the functional assay, appeared to be a partial agonist with little antagonist activity.

Animals↗
PubMed2000

4-[(8-Alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-diethylbenzamides: high affinity, selective ligands for the delta opioid receptor illustrate factors important to antagonist activity.

The tropane derived compounds, 4-[(8-alkyl-8-azabicyclo[3.2.1]octyl-3-yl)-3-arylanilino]-N,N-d iethylbenzamides (5a-d), were synthesized and found to have high affinity and selectivity for the delta receptor. Compounds 5a-d are structurally similar to the full agonist (-)-RTI-5989-54 (3); yet, efficacy studies for compounds in this series (5a-d) reveal greatly diminished agonist activity as well as antagonism not found in piperidine-based compounds like 3.

Benzamides↗
PubMed2000

Comparative neurobiological effects of ibogaine and MK-801 in rats.

Ibogaine is a plant-derived alkaloid with putative 'anti-addictive' properties. Although ibogaine binds to multiple targets in the brain, recent evidence suggests the drug acts as an N-methyl-D-aspartate (NMDA) antagonist similar to MK-801. The purpose of the present study was to compare neurochemical and neuroendocrine effects of ibogaine and MK-801 in vivo. Male rats received either i.p. saline, ibogaine (10 and 100 mg/kg), or MK-801 (0.1 and 1 mg/kg). Groups of rats (N=6-8/group) were decapitated 30 or 60 min after injection. Brains were harvested for analysis of dopamine (DA) and its metabolites, while trunk blood was collected for analysis of plasma corticosterone and prolactin. Ibogaine produced marked dose-dependent reductions in tissue DA with concurrent increases in the metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). This profile of ibogaine-induced effects on DA metabolism was consistently observed in the cortex, striatum, olfactory tubercle, and hypothalamus. MK-801, on the other hand, did not reduce DA levels in any brain region but did cause modest region-specific elevations in DA metabolites. Ibogaine and MK-801 caused comparable elevations in circulating corticosterone, but only ibogaine increased prolactin. The present findings show that the effects of ibogaine on DA neurotransmission and neuroendocrine secretion are not fully mimicked by MK-801. Thus, the wide spectrum of in vivo actions of ibogaine can probably not be explained simply on the basis of antagonism at NMDA receptors.

Animals↗
PubMed2000

Chronic treatment with phentermine combined with fenfluramine lowers plasma serotonin.

As expected on the basis of published research in both humans and animals, treatment with phentermine/fenfluramine lowers plasma 5-hydroxytryptamine [corrected], whereas treatment with phentermine had no significant effect. In light of these findings, future research should focus on mechanisms other than increased plasma 5-hydroxytryptamine [corrected] to explain how fenfluramine increases the risk of primary pulmonary hypertension and valvular heart disease.

Administration, Oral↗
PubMed2000

Neurochemical neutralization of methamphetamine with high-affinity nonselective inhibitors of biogenic amine transporters: a pharmacological strategy for treating stimulant abuse.

The abuse of methamphetamine (METH) and other amphetamine-like stimulants is a growing problem in the United States. METH is a substrate for the 12-transmembrane proteins which function as transporters for the biogenic amines dopamine (DA), serotonin (5-HT), and norepinephrine (NE). Increased release of CNS DA is thought to mediate the addictive effects of METH, whereas increased release of NE in both the peripheral and CNS is thought to mediate its cardiovascular effects. The neurotoxic effects of METH on both dopaminergic and serotonergic nerves requires the transport of METH into the nerve terminals. Thus, transport of METH into nerve terminals is the crucial first step in the production of METH-associated pharmacological and toxicological effects. A single molecular entity which would block the transport of METH at all three biogenic amine transporters might function to neurochemically neutralize METH. This agent would ideally be a high-affinity slowly dissociating agent at all three transporters, and also be amenable to formulation as a long-acting depot medication, such as has been accomplished with an analog of GBR12909. As a first step towards developing such an agent, we established an in vitro assay which selectively detects transporter substrates and used this assay to profile the ability of a lead compound, indatraline, to block the releasing effects of METH and MDMA at the DA, 5-HT, and NE transporters. The major finding reported here is that indatraline blocks the ability of METH and MDMA to release these neurotransmitters. Synapse 35:222-227, 2000. Published 2000 Wiley-Liss, Inc.

Adrenergic Uptake Inhibitors↗
PubMed2000

Resolution of two [(35)S]GTP-gamma-S binding sites and their response to chronic morphine treatment: a binding surface analysis.

The mechanisms by which prolonged exposure to morphine leads to tolerance are not fully understood. We investigated the effects of etorphine (ET) on [(35)S]guanosine 5'-(-thio)-triphosphate ([(35)S]GTP-gamma-S) binding in brains of rats made tolerant to morphine via the implantation of morphine (or placebo) pellets. Binding surface analysis was used to characterize the interactions of ET, Gpp(Np)H and GTP-gamma-S with sites labeled by [(35)S]GTP-gamma-S. Data sets were fitted to one- and two-site binding models using the nonlinear least squares curve fitting program MLAB-PC (Civilized Software, Bethesda, MD, USA). Two binding sites were readily resolved. Chronic morphine significantly increased the B(max) and K(d) of the high affinity binding site. ET stimulated [(35)S]GTP-gamma-S binding in placebo membranes via an increase in the B(max) of the high affinity binding site. In contrast, ET stimulated [(35)S]GTP-gamma-S in chronic morphine membranes via a large decrease in the K(d) of the high affinity site. These results suggest that chronic morphine treatment alters the mechanism by which ET stimulates [(35)S]GTP-gamma-S binding to G-proteins. Since proper G-protein/receptor coupling increases [(35)S]GTP-gamma-S binding via an increase in B(max) values, these results suggest that opioid receptors in chronic morphine membranes are not normally coupled to G-proteins. These findings corroborate earlier studies that reported changes in G-protein function in morphine tolerant animals.

Animals↗
PubMed2000

Effects of phentermine and fenfluramine on extracellular dopamine and serotonin in rat nucleus accumbens: therapeutic implications.

Combined administration of the amphetamine analogs phentermine and fenfluramine (PHEN/FEN) has been used in the treatment of obesity. While these medications are thought to modulate monoamine transmission, the precise neurochemical effects of the PHEN/FEN mixture have not been extensively studied. To assess the mechanism of PHEN/FEN action, in vivo microdialysis studies were performed in the nucleus accumbens of conscious freely moving rats. A series of amphetamine derivatives including phentermine, chlorphentermine, fenfluramine, and PHEN/FEN (1:1 ratio), were infused locally into the accumbens via reverse-dialysis (1, 10, 100 microM) or injected systemically (1 mg/kg, ip). Dialysate samples were assayed for dopamine (DA) and serotonin (5-HT) by high-performance liquid chromatography with electrochemical detection. When infused locally, phentermine preferentially increased extracellular DA, whereas fenfluramine selectively increased extracellular 5-HT. Local administration of chlorphentermine or the PHEN/FEN mixture caused parallel elevations of both transmitters. Analogous results were obtained when the drugs were injected systemically. Phentermine stimulated robust locomotor activity in mice, whereas chlorphentermine and fenfluramine did not. PHEN/FEN caused modest locomotor stimulation after a low dose, but had no effect at the highest dose. Accumulating evidence suggests that chronic drug and alcohol abuse is associated with deficits in both DA and 5-HT neuronal function. Thus, dual activation of DA and 5-HT neurotransmission with monoamine releasing agents may be an effective treatment strategy for substance use disorders, as well as for obesity. Synapse 36:102-113, 2000. Published 2000 Wiley-Liss, Inc.

Amphetamine↗
PubMed2000

Neurochemical neutralization of amphetamine-type stimulants in rat brain by the indatraline analog (-)-HY038.

Amphetamine-type stimulants are substrates for the proteins that serve as transporters for the biogenic amines dopamine (DA), serotonin (5HT), and norepinephrine (NE) and release these neurotransmitters from neurons located in the peripheral and central nervous system. Using indatraline as a lead compound, we sought to develop a long-acting depot medication that would neutralize the deleterious effects of amphetamine-type stimulants. Our first efforts produced (+/-)-HY038, and its two stereoisomers, which are hydroxy-substituted analog of indatraline. The K(i) values for [(3)H]DA reuptake inhibition by (-)-HY038 and (+)-HY038 were 3.2 +/- 0.1 and 32 +/- 1 nM. Similar results were obtained for [(3)H]5HT reuptake inhibition. (-)-HY038 and (+)-HY038 were slightly less potent at inhibiting [(3)H]NE reuptake (K(i) values of 20 +/- 2 and 159 +/- 12 nM). Low doses of (-)-HY038 blunted the ability of AMPH to release [(3)H]DA by shifting the AMPH dose-response curve to the right in a dose-dependent manner. (-)-HY038 also inhibited the ability of (+)-methamphetamine and (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA) to release [(3)H]DA. Low doses of (-)-HY038 blunted the ability of these stimulants to release [(3)H]NE and [(3)H]5HT by shifting their dose-response curves to the right in a manner similar to that seen for inhibition of [(3)H]DA release. These data indicate that (-)-HY038 inhibits the ability of AMPH, (+)-methamphetamine and (+/-)-MDMA to release DA, NE, and 5HT and therefore might have the potential to neutralize the neurotoxic and cardiovascular side-effects of substrate-type stimulants.

Amphetamine-Related Disorders↗
PubMed2000

An open-label study of a functional opioid kappa antagonist in the treatment of opioid dependence.

Several lines of evidence, including the well-established observation that kappa opiate agonists produce dysphoria and psychotomimetic effects in humans, suggest that dysfunction of the endogenous kappa opioid system may contribute to opioid and cocaine addiction. The objective of this open-label study was to determine the effectiveness of a functional kappa antagonist as a treatment for opioid dependence. This was accomplished by combining a partial mu agonist/kappa antagonist (buprenorphine, 4 mg, sublingual) with a mu antagonist (naltrexone, 50 mg by mouth), theoretically leaving kappa antagonism as the major medication effect. Subjects were treatment-seeking heroin-dependent (as per Diagnostic and Statistical Manual of Mental Disorders, 4th ed.) men (41 +/- 7 years old; 19 +/- 8 years heroin use) eligible for methadone maintenance. After inpatient detoxification and a naloxone-challenge test to verify that they were not physically dependent on opioids, subjects received naltrexone. Starting on the fourth day, patients also received liquid buprenorphine. All patients received medication at the clinic 6 days per week and a full program of psychosocial treatment. The major endpoints of the study were: pupil diameter to determine if the mu agonist effects of buprenorphine were blocked by naltrexone, urine toxicology, and retention in treatment. Five patients (33%) completed the 3-month study. Four were abstinent from opioids and cocaine for the entire study, and one was abstinent from opioids and cocaine for the last 9 weeks. Six subjects dropped out due to either minor side effects or disliking the sensation of sublingual buprenorphine. There were no significant changes in pupillary diameter. The positive response to treatment exceeds that expected from naltrexone alone (90% dropout). These promising results suggest that controlled studies of this medication combination should be conducted.

Administration, Sublingual↗
PubMed2000

Uptake and release effects of diethylpropion and its metabolites with biogenic amine transporters.

Three metabolites of diethylpropion (1), (+/-)-2-ethylamino-1-phenyl-propan-1-one (2), (1R,2S)-(-)-N,N-diethylnorephedrine (3a) and (1S,2R)-(-)-N,N-diethylnorephedrine (3b) were synthesized. Their uptake and release effects with biogenic amine transporters were evaluated. A major finding of this study is that the in vivo activity of diethylpropion on biogenic amine transporters is most likely due to metabolite 2 as diethylpropion (1) and the metabolites 3a and 3b showed little or no effect in the assays studied. These studies also revealed that 2 acted as a substrate at the norepinephrine (IC50 = 99 nM) and serotonin transporters (IC50 = 2118 nM) and an uptake inhibitor at the dopamine transporter (IC50 = 1014 nM). The potent action of 2 at the NE transporter supports the hypothesis that amphetamine-type subjective effects may be mediated in part by brain norepinephrine.

Animals↗
PubMed2000

Methamphetamine dependence: medication development efforts based on the dual deficit model of stimulant addiction.

Converging lines of evidence indicate that withdrawal from prolonged exposure to stimulants and alcohol results in synaptic deficits of both dopamine (DA) and serotonin (5-HT). According to the dual deficit model proposed by the authors, DA dysfunction during cocaine or alcohol withdrawal underlies anhedonia and psychomotor retardation, whereas 5-HT dysfunction gives rise to depressed mood, obsessional thoughts, and lack of impulse control. This model predicts that pharmacotherapies which correct only one of the two neurochemical deficits will not be effective. On the other hand, pharmacotherapies which "correct" both of the proposed DA and 5-HT abnormalities should be effective in treating stimulant and alcohol dependence. This paper reviews two approaches, based on the dual deficit model, taken by our laboratory to develop medications to treat stimulant abuse.

Animals↗
PubMed2000

Serotonin transporters, serotonin release, and the mechanism of fenfluramine neurotoxicity.

Administration of d,l-fenfluramine (FEN), or the more active isomer d-fenfluramine (dFEN), causes long-term depletion of forebrain serotonin (5-HT) in animals. The mechanism underlying FEN-induced 5-HT depletion is not known, but appears to involve 5-HT transporters (SERTs) in the brain. Some investigators have postulated that 5-HT release evoked by FEN is responsible for the deleterious effects of the drug. In the present work, we sought to examine the relationship between drug-induced 5-HT release and long-term 5-HT depletion. The acute 5-HT-releasing effects of dFEN and the non-amphetamine 5-HT agonist 1-(m-chlorophenyl)piperazine (mCPP) were evaluated using in vivo microdialysis in rat nucleus accumbens. The ability of dFEN and mCPP to interact with SERTs was assessed using in vitro assays for [3H]-transmitter uptake and release in rat forebrain synaptosomes. Drugs were subsequently tested for potential long-lasting effects on brain tissue 5-HT after repeated dosing (2.7 or 8.1 mg/kg, ip x 4). dFEN and mCPP were essentially equipotent in their ability to stimulate acute 5-HT release in vivo and in vitro. Both drugs produced very selective effects on 5-HT with minimal effects on dopamine. Interestingly, when dFEN or mCPP was administered repeatedly, only dFEN caused long-term 5-HT depletion in the forebrain at 2 weeks later. These data suggest that acute 5-HT release per se does not mediate the long-term 5-HT depletion associated with dFEN. We hypothesize that dFEN and other amphetamine-type releasers gain entrance into 5-HT neurons via interaction with SERTs. Once internalized in nerve terminals, drugs accumulate to high concentrations, causing damage to cells. The relevance of this hypothesis for explaining clinical side effects of FEN and dFEN, such as cardiac valvulopathy and primary pulmonary hypertension, warrants further study.

Analysis of Variance↗
PubMed2000

Noribogaine (12-hydroxyibogamine): a biologically active metabolite of the antiaddictive drug ibogaine.

Ibogaine (IBO) is a plant-derived alkaloid that is being evaluated as a possible medication for substance use disorders. When administered peripherally to monkeys and humans, IBO is rapidly converted to an o-demethylated metabolite, 12-hydroxyibogamine (NORIBO). We have found in rats that peak blood levels of NORIBO can exceed those of the parent compound, and NORIBO persists in the bloodstream for at least 24 h. Surprisingly few studies have examined the in vivo biological activity of NORIBO. In the present series of experiments, we compared the effects of intravenous (i.v.) administration of IBO and NORIBO (1 and 10 mg/kg) on unconditioned behaviors, circulating stress hormones, and extracellular levels of dopamine (DA) and serotonin (5-HT) in the nucleus accumbens of male rats. IBO caused dose-related increases in tremors and forepaw treading, whereas NORIBO did not. Both IBO and NORIBO produced significant elevations in plasma corticosterone and prolactin, but IBO was more potent as a stimulator of corticosterone secretion. Neither drug affected extracellular DA levels in the nucleus accumbens. However, both IBO and NORIBO increased extracellular 5-HT levels, and NORIBO was more potent in this regard. The present data demonstrate that NORIBO is biologically active and undoubtedly contributes to the in vivo pharmacological profile of IBO in rats. Most importantly, NORIBO appears less likely to produce the adverse effects associated with IBO (i.e., tremors and stress-axis activation), suggesting that the metabolite may be a safer alternative for medication development.

Analysis of Variance↗