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Director's Report to the National Advisory Council on Drug Abuse
May, 2001

Research Findings

Intramural Research

Chemistry & Drug Metabolism Section, Clinical Pharmacology & Therapeutics Research Branch

Blockade of Effects of Smoked Marijuana by the CB1-Selective Cannabinoid Receptor Antagonist SR141716

SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Λ-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. A single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time X concentration curve. SR141716 was well tolerated by all subjects. SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana. Huestis, M.A., Gorelick, D.A., Heishman, S.J., Preston, K.L., Nelson, R.A., Moolchan, E.T. and Frank, R.A. Archives of General Psychiatry, 58, pp. 322-328, 2001.

Peptide-Peptide Interaction by MALDI

Matrix assisted laser desorption/ionization mass spectrometry (MALDI) was used to study peptide-peptide interaction. The interaction was seen when 6-aza-2-thiothymine was used for matrix (pH 5.4), but was disrupted when -cyano-4-hydroxycinnamic acid (pH 2.0) was used. In the present study we show that dynorphin, an opioid peptide, and 5 of its fragments that contain two adjacent basic residues (Arg6 and Arg7), all interact non-covalently with peptides that contain two to five acidic residues (Asp or Glu). Two other non-related peptides containing Two (Arg-Arg) or Three (Arg-Lys-Arg) adjacent basic amino acid residues show the same behavior. However peptides containing two adjacent lysines or histidines did not. The non-covalent bonding is so stable that digestion with trypsin, only cleaved the peptides at the carboxyl-terminus of basic residues that were not involved in hydrogen bonding with the acidic residues. In an equimolar mixture of dynorphin, its fragments and an acidic peptide (mini-gastrin), the acidic peptide formed ionic bonds preferentially with dynorphin. However, if the concentration of mini-gastrin was increased 10 fold, non-covalent interaction was seen with dynorphin and all its fragments. In the absence of dynorphin, mini-gastrin formed non-covalent complexes with all dynorphin fragments. These findings suggest that conformation, equilibrium and concentration do play a role in the occurrence of peptide-peptide interaction. The fact that the ionic bonds could not be disrupted by enzymatic digests, that conformation and concentration seem to influence the complex formation, and that the complex did not form with fragments of dynorphin that did not contain residues 6 and 7, and with fragments of dynorphin where Arg7 was mutated to a phenylalanine residue, strongly suggests that peptide-peptide interaction does occur, and can be studied by MALDI if physiologic pH is maintained. Woods, A.S. and Huestis, M.A. Journal of Mass Spectrometry, 12, pp. 88-96, 2001.

Monitoring Opiate Use in Substance Abuse Treatment Patients

Although urine testing remains the standard drug use monitoring method, sweat testing for drugs of abuse is increasing, especially in criminal justice programs. One reason for this increase is that sweat testing offers the possibility for widening the detection window compared to urine testing. This study was designed to compare the efficacy of sweat versus urine for detecting drug use. Paired sweat patches that were applied and removed weekly (on Tuesdays) were compared to 3-5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays (355 matched sweat and urine specimen sets) in 44 patients in a methadone maintenance outpatient treatment program. All patches (N = 1010) were extracted in 2.5 mL of solvent and analyzed by ELISA immunoassay (cutoff concentration 10 ng/mL). A subset (389) of patches was analyzed by GC/MS. Urine specimens were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL). Opiates were detected in 22.5% of the sweat patches with the ELISA screen. Eighty-nine percent of the screen-positive sweat patches were confirmed by GC-MS for heroin, 6-acetylmorphine, morphine and/or codeine. Heroin and/or 6-acetylmorphine were detected in 78.1% of the GC/MS positive sweat patches. There were 13.5% false negative and 7.9% false positive sweat results as compared to urine tests. Analysis of sweat patches provides an alternate method for objectively monitoring drug use and provides an advantage over urine drug testing by monitoring an individual's drug use over an extended period of time. However, the percentage of false negative results, at least in this treatment population, indicates that weekly sweat testing may be slightly less sensitive than thrice weekly urine testing in detecting opiate use. Huestis, M.A., Cone, E.J., Wong, C.J., Umbricht, A. and Preston, K.L. Journal of Analytical Toxicology, 24, pp. 509-521, 2000.

Cocaine and Metabolite Elimination Patterns in Chronic Cocaine Users During Cessation

Several reports suggest a prolonged elimination of cocaine and metabolites after chronic use compared to single or occasional use. This study was designed to measure the half-lives of cocaine in plasma and saliva of individuals who consume cocaine on a frequent basis. We investigated the disposition and elimination patterns of cocaine and metabolites in the body fluids of chronic high-dose cocaine users during acute cessation of use. Plasma and saliva specimens were collected over a 12 h period during cessation and analyzed by gas chromatography-mass spectrometry. Pharmacokinetic parameters were derived by noncompartmental analysis of plasma and saliva data. Results indicated a cocaine terminal T1/2 of 3.8 hours in plasma and 7.9 hours in saliva. The terminal T1/2 of benzoylecgonine was 6.6 hours in plasma and 9.2 hours in saliva. Compared with prior studies of acute low-dose cocaine administration, these findings suggest that cocaine's half-life is longer in active street users than in occasional users though the half-life of its main metabolite benzoylecgonine remains similar (as do cocaine saliva-to-plasma ratios). Thus, regular use of cocaine appears to alter the disposition and elimination of cocaine when compared to single or occasional use. Moolchan, E.T., Cone, E.J., Wtsadik, A., Huestis, M.A., and Preston, K.L. Journal of Analytical Toxicology, 24, pp. 458-466, 2000.

Brain Imaging Section, Neuroimaging Research Branch

Volume of Lateral Ventricle in Bipolar I Patients is Nearly Twice as Large as the Volume in Patients with Bipolar II Disorder

A quantitative magnetic resonance imaging comparison of bipolar I and bipolar II patients was undertaken because no previous quantitative assessments of bipolar II patients have been documented and the number of quantitative studies of bipolar I patients is small. Magnetic resonance imaging was used to estimate volume of the temporal lobe, hippocampus, and the lateral ventricle in 25 bipolar I disorder, 22 bipolar II disorder, and 19 control subjects. There were no significant differences in volume estimates for the temporal lobe and hippocampus between groups. In contrast, the lateral ventricle area and the lateral ventricle to cerebrum area ratio were approximately twice as large in the bipolar I patients as the other groups in the left hemisphere only. The results suggest that subjects diagnosed with bipolar I disorder, particularly in males, may show neurobiological alterations different from patients with bipolar II disorder or control subjects. Hauser, P., Matochik, J.A., Altshuler, L.L., Denicoff, K.D., Conrad, A., Li, X., and Post, R.M. Journal of Affective Disorders, 60, pp. 25-32, 2000.

Methadone-maintained Former Heroin Addicts Have Lower Specific Binding of [18F] cyclofoxy, an Opioid Antagonist, in Brain Areas Related to Drug Addiction

Positron emission tomography using tracer amounts of [18F]cyclofoxy, an opioid antagonist that labels mu and kappa receptors, was used to measure opioid receptor binding in 14 stabilized methadone-maintained former heroin addicts and 14 healthy controls. Specific binding of [18F]cyclofoxy was lower by 19 to 32% in methadone-maintained subjects compared to controls in the thalamus, amygdala, caudate nucleus, putamen, and the anterior cingulated cortex. Lower specific binding in the caudate nucleus and putamen was correlated with methadone plasma levels, suggesting that lower binding may be related to receptor occupancy with methadone and that significant numbers of opioid receptors may be available to function in their normal physiological roles. Kling, M.A., Carson, R.E., Borg, L., Zametkin, A., Matochik, J.A., Schluger, J., Herscovitch. P., Rice, K.C., Ho, A., and Kreek, M.J. Journal of Pharmacology and Experimental Theraputics, 295, pp. 1070-1076, 2000.

Development and Plasticity Section, Cellular Neurobiology Research Branch

Motor Activity-Mediates Partial Recovery in Ischemic Rats

Spontaneous partial recovery in motor and/or cognitive dysfunctions in stroke patients has been documented, but the factors that affect such functional improvement have not been well elucidated. The present study demonstrates that repeated behavioral testing (daily or once a week over a period of 4 weeks) promoted partial recovery from motor asymmetry in adult ischemic rats. In contrast, ischemic animals that were only tested once every 2 weeks or once after 4 weeks did not show such partial recovery. These results suggest that repeated behavioral testing (i.e., increased use of the ischemia-affected limbs and body parts) may contribute to partial recovery of motor deficits following an experimental stroke, even in the absence of pharmacological therapeutic intervention. Borlongan, C.V. NeuroReport, 18, pp. 4063-4067, 2000.

Cellular Neurophysiology Section, Cellular Neurobiology Research Branch

Methamphetamine Potentiates Ischemic Brain Injury

Previous studies have indicated that both methamphetamine (MA) and ischemia/reperfusion injuries involve reactive oxygen species formation and activation of apoptotic mechanism. It is possible that MA may have a synergistic or additive effect with stroke-induced brain damage. The purpose of this study was to investigate if administration of MA in vivo would potentiate ischemic brain injury. Adult CD-1 mice were treated with MA (10 mg/kg) or saline (i.p., 4 times, each dose two hours apart). Animals were later anesthetized with chloral hydrate and then placed in stereotaxic frame. A subset of animals received intracerebral administration of glial cell line-derived neurotrophic factor (GDNF). The right middle cerebral artery (MCA) and bilateral carotids were transiently occluded for 45 minutes. Regional cerebral blood flow was measured by Laser Doppler. Animals were sacrificed for tri-phenyl-tetrazolium chloride (TTC) staining and p53 mRNA Northern blot assay after 24 hours of reperfusion. Cortical and striatal GDNF levels were assayed by ELISA. Investigators found that pretreatment with MA increased ischemia-induced cerebral infarction. Ischemia or MA alone enhanced p53 mRNA expression. Moreover, MA potentiated the expression of p53 mRNA in the ischemic mouse brain. MA pretreatment decreased GDNF levels in ischemic striatum. Intracerebral administration of GDNF before ischemia reduced MA-facilitated infarction. These data indicate that MA exacerbates ischemic insults in brain, perhaps through the inhibition of GDNF-mediated pathways, and suggest that MA may antagonize endogeneous neuroprotective pathways as part of its mechanism of action. Wang, Y., Hayashi, T., Chang, C.F., Chiang, Y.H., Tsao, L.I., Su, T.P., Borlongan, C.V., and Lin, S.Z. Stroke, 32, pp. 775-782, 2001.

Molecular Neuropsychiatry Section, Cellular Neurobiology Research Branch

Delta Opioid Peptide [D-Ala2, D-Leu5]Enkephalin Causes a Near Complete Blockade of the Neuronal Damage Caused by a Single High Dose of Methamphetamine: Examining the Role of p53

The delta opioid peptide [D-Ala2, D-Leu5]enkephalin (DADLE) has been reported to block the neurotoxicity induced by multiple administrations of a moderate dose of methamphetamine (METH). IRP scientists examined in this study if DADLE might block the neurotoxicity caused by a single high dose of METH in CD-1 mice. The levels of dopamine transporter (DAT), tyrosine hydroxylase (TH), major biogenic amines including DA, 5-hydroxytryptamine (5-HT), and their metabolites were examined. In addition, since the tumor suppressor p53 has been implicated in the neurotoxicity of METH, this study also examined the levels of p53 mRNA and protein affected by METH and DADLE. METH (25 mg/kg, i.p.) caused significant losses of DAT, TH, DA, 3,4-dihydroxyphenylacetic acid (DOPAC), and 5-HT in the striatum within 72 h. The administration of a single dose of DADLE (20 mg/kg, i.p., 30 min before METH) caused a complete blockade of all losses induced by METH except for that of the DA content (an approximately 50% blockade). DADLE did not affect the changes of rectal temperature induced by the administration of the high dose of METH. METH increased p53 mRNA in the striatum and the hippocampus of CD-1 mouse. DADLE abolished the p53 mRNA increase caused by METH. METH tended to increase the p53 protein level at earlier time points. However, METH significantly decreased the p53 protein level by about 30% at the 72-h time point. DADLE blocked both the increase of p53 mRNA and the decrease of p53 protein caused by METH. These results demonstrate a neuroprotective effect of DADLE against the neuronal damage and the alteration of p53 gene expression caused by a single high dose of METH. The results also indicate an apparent discordance between the protein level of p53 and the neurotoxicity caused by a high dose of METH. Hayashi, T., Hirata, H., Asanuma, M., Ladenheim, B., Tsao, L.I., Cadet, J.L. and Su, T.P. Synapse 39(4), pp. 305-312, 2001.

Peroxynitrite Plays a Role in Methamphetamine-induced Dopaminergic Neurotoxicity: Evidence from Mice Lacking Neuronal Nitric Oxide Synthase Gene or Overexpressing Copper-Zinc Superoxide Dismutase

The use of methamphetamine (METH) leads to neurotoxic effects in mammals. These neurotoxic effects appear to be related to the production of free radicals. To assess the role of peroxynitrite in METH-induced dopaminergic damage, IRP scientists investigated the production of 3-nitrotyrosine (3-NT) in the mouse striatum. The levels of 3-NT increased in the striatum of wild-type mice treated with multiple doses of METH (4 x 10 mg/kg, 2 h interval) as compared with the controls. However, no significant production of 3-NT was observed either in the striata of neuronal nitric oxide synthase knockout mice (nNOS -/-) or copper-zinc superoxide dismutase overexpressed transgenic mice (SOD-Tg) treated with similar doses of METH. The dopaminergic damage induced by METH treatment was also attenuated in nNOS-/- or SOD-Tg mice. These data further confirm that METH causes its neurotoxic effects via the production of peroxynitrite. Imam, S.Z., Newport, G.D., Itzhak, Y., Cadet, J.L., Islam, F., Slikker, W. and Ali, S.F. J Neurochem., 76(3), pp.745-749, 2001.

Effects of Methamphetamine-induced Neurotoxicity on the Development of Neural Circuitry: A Hypothesis

Exposure of the developing brain to methamphetamine has well-studied biochemical and behavioral consequences. IRP scientists reviewed: (1) the effects of methamphetamine on mature serotonergic and dopaminergic pathways; (2) the mechanisms of methamphetamine neurotoxicity and (3) the role of serotonergic and dopaminergic signaling in sculpting developing neural circuitry. Consideration of these data suggest the types of neural circuit alterations that may result from exposure of the developing brain to methamphetamine and that may underlie functional defects. Frost, D.O. and Cadet, J.L. Brain Res Rev., 34(3), pp. 103-118, 2000.

African-American Teen Smokers: Issues to Consider for Cessation Treatment

Previous reports have indicated ethnic differences in both tobacco-related morbidity and treatment outcome for smoking cessation among adults. IRP investigators assessed smoking-related characteristics in African-American and non-African American teenagers applying to a cessation trial. 115 teens (15.9 +/- 1.8 years, 68% females, 27% African-American) responded via telephone to media ads. Self-reported sociodemographic, medical and smoking-related data were obtained to determine pre-eligibility for a full intake screen prior to trial participation. Compared to non-African American, African American teen applicants were older (16.4 +/- 1.7 years versus 15.6 +/- 1.6; p = 0.015), had lower Fagerstrom Test for Nicotine Dependence (FTND) scores (5.3 +/- 2.3 versus 6.1 +/- 1.8; p = 0.018, ANOVA controlling for age) and smoked fewer cigarettes on the weekend (27 +/- 16 versus 38 +/- 17; p = 0.001). African American teens reported similar duration of smoking (3.3 +/- 1.4 versus 3.1 +/- 1.5 years) and time elapsed between first cigarette ever smoked and daily smoking (0.7 +/- 0.9 versus 0.6 +/- 0.7 years). African American and non-African American teens had similar motivation to quit scores and frequency of reported health problems (e.g., asthma, psychiatric conditions). These data suggest that cessation treatment programs designed for African American youth should include lower Fagerstrom-defined levels, and possibly other criteria for tobacco dependence. These observations also highlight the importance of ethnocultural issues in treatment research programs. Moolchan, E.T., Berlin, I., Robinson, M.L., and Cadet, J.L. J Natl Med Assoc., 92(12), pp. 558-562, 2000.

Behavioral Neuroscience Section, Behavioral Neuroscience Research Laboratory

Role of Leptin in Relapse to Heroin Seeking Induced by Food Deprivation

Studies in rats have shown that intermittent footshock stress reinstates drug seeking after prolonged drug-free periods. Recently, IRP investigators found that another environmental stressor, acute 1-day food deprivation, potently reinstates heroin seeking in rats. Here they report that this effect of food deprivation can be blocked by leptin, a hormone involved in the regulation of energy balance and food intake. Rats were trained to self-administer heroin (0.05-0.1 mg/kg/infusion, IV, three 3-hr sessions/day) for 8-10 days. The heroin-reinforced behavior was then extinguished for 10-13 days during which lever presses had no reinforced consequences. Subsequently, rats were tested for reinstatement after one day of food deprivation (Experiment 1), or exposure to intermittent footshock (15 min, 0.6 mA) and heroin priming injections (0.25 mg/kg, SC) (Experiment 2). Acute food deprivation reinstated heroin seeking, an effect that was attenuated by leptin (2 or 4 g/rat, ICV; 2 infusions, given 21 hr and 20-30 min before the start of the test sessions). In contrast, leptin had no effect on reinstatement of heroin seeking induced by intermittent footshock or priming injections of heroin. These data indicate that food deprivation can provoke relapse to heroin seeking via a leptin-dependent mechanism, which is not involved in relapse induced by footshock stress or reexposure to heroin. Shalev, U., Yap, J. and Shaham, Y. The Journal of Neuroscience, 21, RC129, pp. 1-5, 2001.

Preclinical Pharmacology Section, Behavioral Neuroscience Research Laboratory

Self-administration of Remifentanil, an Ultra-Short Acting Opioid, Under Continuous-Reinforcement and Progressive-Ratio Schedules

It has been proposed that there is a relationship between a drug's duration of action and its effectiveness as a reinforcer. Remifentanil is an opioid with a half-life of less than a minute. To evaluate the role of duration of action in drug self-administration we compared the ability of remifentanil to maintain self-administration with the longer acting opioid heroin. On a continuous reinforcement schedule, inter-infusion intervals for both drugs increased monotonically as a function of dose, with the remifentanil curve being considerably flatter. That is, at higher doses animals were able to respond at higher rates when remifentanil was used to maintain responding. Under a progressive ratio schedule, the highest break points maintained by remifentanil and heroin were similar. Therefore, although rates of self-administration are clearly influenced by a drug's duration of action, the ability for a drug to maintain responding under intermittent schedules of reinforcement may be independent of duration of action. Panlilio, L.V. and Schindler, C.W. Psychopharmacology, 150, pp. 61-66, 2000.

Medicinal Chemistry and Psychobiology Sections, Medications Discovery Research Branch

Highly Selective Chiral N-substituted 3α-[bis(4'-fluorophenyl)methoxy]Tropane Analogues for the Dopamine Transporter: Synthesis and Comparative Molecular Field Analysis

In a continuing effort to further characterize the role of the dopamine transporter (DAT) in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3α-[bis(4'-fluorophenyl)methoxy]tropane (4',4"-diF-BZT) has been prepared, as selective DAT ligands. These novel compounds displaced [3H]WIN 35,428 binding from DAT, in rat caudate putamen, with Ki values ranging from 14.0 to 477 nM. Previously, it was reported that 4',4"-diF-BZT, demonstrated a significantly higher affinity for DAT than the parent drug, benztropine (BZT). However, 4',4"-diF-BZT remained nonselective over muscarinic m1 receptors (DAT, Ki=11.8 nM; m1, Ki=11.6 nM) which could potentially confound the interpretation of behavioral data, for this compound and other members of this series. Thus, significant effort has been directed toward developing analogs that retain high affinity at DAT but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 4',4"-diF-BZT with the phenyl-n-butyl substituent, retention of high binding affinity at DAT (Ki=8.51 nM) while decreasing affinity at muscarinic receptors (Ki=576 nM) was achieved, resulting in a 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analog (S)-(N-2-amino-3-methyl-n-butyl)-3α-[bis(4'-fluorophenyl)methoxy] tropane, showing a 136-fold selectivity for DAT vs. muscarinic m1 receptors (Ki=29.5 nM vs. Ki=4020 nM, respectively). In addition, a Comparative Molecular Field Analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted-4',4"-diF-BZT analogues prepared with their 3D-structural features. The best model (q2 = 0.746) was used to accurately predict binding affinities of compounds in the training set and in a test set. The CoMFA coefficient contour plot for this model, which provides a visual representation of the chemical environment of the binding domain of DAT, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors. Robarge, M.J., Agoston, G.E., Izenwasser, S., Kopajtic, T., George, C., Katz, J.L., and Newman, A.H. Journal of Medicinal Chemistry, 43, pp. 1085-1093, 2000.

2D QSAR Modeling of Dopamine Transporter Inhibitor Affinity Using Genetic Algorithm Variable Selection of Molconn Z Descriptors

Novel approaches towards both understanding the activity of inhibitors of the dopamine transporter (DAT) and the identification of novel inhibitors that may be of therapeutic potential have been taken in order to further elucidate the role of the DAT in the pharmacology and abuse potential of cocaine. IRP scientists' most recent studies towards these ends have made use of two-dimensional (2D) Quantitative Structure Activity Relationship (QSAR) methods in order to develop predictive models that correlate structural features of DAT ligands to their biological activities. Specifically, they have adapted the method of Genetic Algorithms-Partial Least Squares (GA-PLS) to the task of variable selection of the descriptors generated by the software Molconn Z. As the successor to the program Molconn X, which generated 462 descriptors, Molconn Z provides 749 chemical descriptors. By employing genetic algorithms in optimizing the inclusion of predictive descriptors, they have successfully developed a robust model of the DAT affinities of 70 structurally diverse DAT ligands. This model, with an exceptional q2 value of 0.85, is nearly 25% more accurate in predictive value than a comparable model derived from Molconn X-derived descriptors (q2 = 0.69). Utilizing activity-shuffling validation methods, they have demonstrated the robustness of both this DAT inhibitor model and their QSAR method. Moreover, they have extended this method to the analysis of dopamine D1 antagonist affinity and serotonin ligand efficacy, illustrating the significant improvement in q2 for a variety of data sets. Finally, they have employed their method in performing a search of the National Cancer Institute database based upon activity predictions from their DAT model. They report the preliminary results of this search, which has yielded five compounds suitable for lead development as novel DAT inhibitors. Hoffman, B.T., Kopajtic, T., Katz, J.L., and Newman, A.H. Journal of Medicinal Chemistry, 43, pp. 4151-4159, 2000.

Structure-Activity Relationships at the Monoamine Transporters and Muscarinic Receptors for N-substituted-3α-[3'-Chloro-, 4'-Chloro-, 4',4"-diChloro-substituted) diphenyl] Methoxytropanes

The design, synthesis and evaluation of benztropine (BZT) analogs have provided potent and selective probes for the dopamine transporter (DAT). Structure-activity relationships have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the BZT analogs in animal models of cocaine abuse, has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the BZT analogs, do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors, in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporter as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl and butylphenyl) analogs of 3'-chloro-, 4'-chloro- and 4,4"-dichloro-BZT were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from DAT, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter and [3H]pirenzepine from muscarinic m1 receptors. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of structural/binding profile that might be targeted as a potential treatment for cocaine abuse. Newman, A.H., Robarge, M.J., Howard, I.M., Wittkopp, S.L., George, C., Kopajtic, T., Izenwasser, S., and Katz, J.L. Journal of Medicinal Chemistry, 44, pp. 633-640, 2001.

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