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J L Katz

Publications and source records attributed to J L Katz.

At least 19 recordsLinked to original sources
PubMed2004

DNA interstrand cross-linking by a mycotoxic diepoxide.

The diepoxide mycotoxin (2R, 3R, 8R, 9R)-4,6-decadiyne-2,3:8,9-diepoxy-1,10-diol (repandiol) was both isolated from the mushroom Hydnum repandum and synthesized de novo. Repandiol was found to form interstrand cross-links within a restriction fragment of DNA, linking deoxyguanosines on opposite strands primarily within the 5'-GNC and 5'-GNNC sequences preferred by diepoxyoctane. However, repandiol was a significantly less efficient cross-linker than either of the diepoxyalkanes (diepoxyoctane and diepoxybutane) to which it was compared.

Alkynes↗
PubMed2003

Size and shape of mineralites in young bovine bone measured by atomic force microscopy.

Atomic force microscopy (AFM) was used to obtain three-dimensional images of isolated mineralites extracted from young postnatal bovine bone. The mean mineralite size is 9 nm x 6 nm x 2.0 nm, significantly shorter and thicker than the mineralites of mature bovine bone measured by the same technique. Mineralites of the young postnatal bone can be accommodated within the hole zone regions of a quasi-hexagonally packed collagen fibril in the fashion described by Hodge [9] in which laterally adjacent hole zone regions form continuous "channels" across the diameter of a fibril for a distance of at least 10 nm. Deposition of mineralites of the size noted above in this void volume of the fibrils would result in little or no distortion of the collagen molecules or supramolecular structure of the collagen fibril. The new AFM data supporting this claim is consistent with findings obtained by electron microscopy and low-angle x-ray and neutron diffraction that mineralites formed within collagen fibrils during initial stages of calcification occur within the hole zone region. However, the deposition of additional mineralites in the intermolecular spaces between collagen molecules in the overlap region of the fibrils would significantly distort the fibrils since the space available between adjacent molecules is considerably less than even the smallest dimension of the mineralites.

Animals↗
PubMed2003

Comparison of the discriminative-stimulus effects of SKF 38393 with those of other dopamine receptor agonists.

The dopamine D(1)-like receptor agonists have traditionally been defined molecularly by their efficacy in stimulating adenylyl cyclase. However, evidence correlating the effectiveness of these drugs in behavioral assays and their effectiveness biochemically has not been forthcoming. The present study compared the discriminative-stimulus effects of the D(1)-like partial agonist SKF 38393 with several other D(1)-like agonists, an indirect agonist, cocaine, and a D(2)-like agonist, quinpirole. Rats were trained under a fixed-ratio 30-response schedule to discriminate SKF 38393 (5.6 mg/kg) from vehicle. Under this schedule, 30 consecutive responses on one of two keys were reinforced with food presentation after a pre-session injection of 5.6 mg/kg SKF 38393, and 30 consecutive responses on the alternative key were reinforced after saline injection. When daily performances were stable, substitution patterns for several compounds were assessed during test sessions in which 30 consecutive responses on either key were reinforced. Quinpirole and cocaine each produced saline-appropriate responding. In contrast, the D(1)-like agonists, SKF 75670 and SKF 77434, fully substituted for SKF 38393. Curiously, SKF 82958, which is considered a full agonist based on adenylyl cyclase assays, was less effective in substituting for SKF 38393 (maximum drug-appropriate responding 66%) than was the partial agonist SKF 75670. The present results suggest that second messenger effects other than stimulation of adenylyl cyclase may play an important role in the behavioral effects of dopamine D(1)-like agonists.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
PubMed2001

[3-cis-3,5-Dimethyl-(1-piperazinyl)alkyl]-bis-(4'-fluorophenyl)amine analogues as novel probes for the dopamine transporter.

In a continuing effort to identify novel probes with which to study the dopamine transporter (DAT), we discovered that the sigma receptor antagonist, rimcazole, binds with moderate affinity (K(i)=224nM) to the DAT. The results from previous SAR studies suggested that substitution of the carbazole ring system of rimcazole with bis-(4'-fluorophenyl)amine might improve binding affinity and selectivity for the DAT. Thus, a novel series of [3-cis-3,5-dimethyl-(1-piperazinyl)alkyl]bis-(4'-fluorophenyl)amines were synthesized. The most potent compound in this series (9b) displaced [3H]WIN 35,428 binding in rat caudate-putamen (K(i)=17.6nM) with comparable affinity to GBR 12909. Despite high-affinity binding at DAT, and structural similarity to GBR 12909, preliminary studies suggest 9b behaves more like rimcazole than GBR 12909 and does not demonstrate cocaine-like psychostimulant behavior in mice.

Animals↗
PubMed2001

Novel tropane-based irreversible ligands for the dopamine transporter.

3alpha-(diphenylmethoxy)tropane (benztropine) and its analogues are tropane ring-containing dopamine uptake inhibitors that display binding and behavioral profiles that are distinct from cocaine. We previously prepared a benztropine-based photoaffinity label [125I]-(N-[4-(4'-azido-3'-iodophenyl)butyl]-3alpha-[bis(4'-fluorophenyl)methoxy]tropane, [125I]1, that covalently attached to the 1-2 transmembrane spanning region of the dopamine transporter (DAT). This was in contrast to the 4-7 transmembrane spanning region labeled by a cocaine-based photoaffinity label, [125I] 2 (RTI 82). To characterize further these different binding domains, photoaffinity ligands that had the 4'-azido-3'-iodophenyl substituent extended from the same position on the tropane ring were desirable. Thus, identification of the optimal alkyl linker between this substituent and the tropane nitrogen in the benztropine series was investigated to ultimately prepare the identical N-substituted analogue of 2. In this pursuit, the N-[4-(4'-azido-3'-iodophenyl)propyl] analogue of 3alpha-[bis(4'-fluorophenyl)methoxy]tropane (9a) was synthesized as well as two isothiocyanate analogues that do not require photoactivation (10a,b) for irreversible binding. The synthesis of these target compounds was achieved using a modification of the strategy developed for 1. Evaluation of these compounds for displacing [3H]WIN 35 428 binding at DAT in rat caudate putamen revealed that the 4'-azido-3'-iodophenylbutyl substituent, found in 1, provided optimal binding affinity and was chosen to replace the N-CH3 group on 2. Both the 4'-azido-3'-iodophenyl- and the 4'-isothiocyanatophenylbutyl analogues of 2 (25 and 26, respectively) were synthesized. Both products bound to DAT with comparable potency (IC(50) = 30 nM) to RTI 82 (2). In addition, compound 26 demonstrated wash-resistant displacement of [3H]WIN 35 428 in HEK 293 cells stably transfected with hDAT. These ligands will provide important tools for further characterizing the binding domains for tropane-based dopamine uptake inhibitors at the DAT.

Animals↗
PubMed2001

Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3alpha-(3'-chloro-, 4'-chloro-, and 4',4''-dichloro-substituted-diphenyl)methoxytropanes.

The design, synthesis, and evaluation of 3alpha-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues 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 benztropine analogues 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 transporters 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) analogues of 3'-chloro-, 4'-chloro-, and 4,4''-dichloro-3alpha-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from the dopamine transporter, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter, and [3H]pirenzepine from muscarinic m1 receptors. SARs were developed and compared to a series of N-substituted-3alpha-(bis-4'-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4',4''-difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3alpha-(bis-4'-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. 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 binding profile that might be targeted as a potential treatment for cocaine abuse.

Animals↗
PubMed2001

Can steroid use be a precipitant in the development of an eating disorder?

OBJECTIVE: Corticosteroids have a wide range of clinical indications in the treatment of both acute and chronic medical illnesses, and weight gain is a well-documented side effect of their use. In this paper, we describe eight individuals with an eating disorder, which appeared following steroid administration for a medical condition. METHOD: These findings, support the possibility that the excessive weight gain resulting from steroid use can be a precipitating factor in the development of an eating disorder, particularly among female adolescents and young women who are preoccupied with their appearance and weight. RESULTS: Physicians caring for women receiving corticosteroids should therefore familiarize themselves with these patients' pre-morbid and current eating habits, as well as their weight, dieting and body image histories. DISCUSSION: The relevance of these cases for furthering our understanding of the development and treatment of eating disorder is also discussed.

Adolescent↗
PubMed2001

Micromechanics of the dentin/adhesive interface.

Scanning acoustic microscopy (SAM) was used in the burst mode at 400 MHz, nominal lateral resolution 2.5 microm, to study the micromechanical properties of the dentin/adhesive interface. Corresponding specimens from the same tooth were investigated using mu Raman spectroscopy, light microscopy, and scanning electron microscopy.12 The elastic moduli of the components of the dentin/adhesive interface were determined by comparing the recorded acoustic impedance values to a calibration curve generated on standard materials. The standard materials, which include polypropylene, Teflon, PMMA, pyrex glass, aluminum, titanium, and stainless steel, provide the appropriate range of acoustic impedance values. The elastic moduli of the components of the dentin/adhesive interface are: partially demineralized dentin, 13 Gpa; mineralized dentin, 28 GPa; adhesive, 5.0 GPa; and unprotected protein at the interface < 2.0 GPa.

Dental Materials↗
PubMed2001

Further studies of the reinforcing effects of benztropine analogs in rhesus monkeys.

RATIONALE: Several halogenated analogs of benztropine (BZT) have previously been characterized as potent DA uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. In a previous study using a fixed-ratio 10 schedule, two chloro-analogs (3'-Cl-BZT and 4'-Cl-BZT) maintained i.v. self-administration in monkeys but appeared to be weak positive reinforcers. OBJECTIVES: The present experiments were designed to test the hypothesis that 3'-Cl-BZT and 4'-Cl-BZT are relatively weak reinforcers by evaluating reinforcing effects under increased response requirements. To examine further the effect of this halogen substitution on self-administration, 3',4"-diCl-BZT was also evaluated for reinforcing effects. METHODS: Four rhesus monkeys self-administered cocaine (0.03 mg/kg per injection, i.v.) under a fixed-ratio 25 (FR25) schedule until stable responding was established. Saline, various doses of cocaine (0.003-0.2 mg/kg per injection), the BZT analogs (0.012-0.2 mg/kg per injection), GBR 12909 (0.012-0.2 mg/kg per injection), and compounds with known reinforcing effects (d-amphetamine, morphine, pentobarbital, ketamine) were then made available for self-administration. Various doses (0.01-0.3 mg/kg per injection) of the compounds that maintained self-administration under the FR schedule were then substituted for cocaine (0.1 mg/kg per injection) under progressive-ratio (PR) schedules. RESULTS: Reinforcing effects were evident under the FR schedule for 3'-Cl-BZT, 4'-Cl-BZT, GBR 12909, and the control compounds, but not by 3',4"-diCl-BZT. Results with the PR suggested that the rank order of these compounds for their effectiveness as reinforcers was cocaine > GBR 12909 > 3'-Cl-BZT = 4'-Cl-BZT >> 3',4"-diCl-BZT. CONCLUSIONS: This study confirms and extends previous results suggesting that compounds with high DAT affinity can have strong, moderate, weak, or no effectiveness as reinforcers. The mechanisms that may underlie this variation in reinforcing effectiveness of these DAT ligands remain to be established.

Animals↗
PubMed2001

Dopamine transporter binding without cocaine-like behavioral effects: synthesis and evaluation of benztropine analogs alone and in combination with cocaine in rodents.

RATIONALE: Previous SAR studies demonstrated that small halogen substitutions on the diphenylether system of benztropine (BZT), such as a para-Cl group, retained high affinity at the cocaine binding site on the dopamine transporter. Despite this high affinity, the compounds generally had behavioral effects different from those of cocaine. However, compounds with meta-Cl substitutions had effects more similar to those of cocaine. OBJECTIVES: A series of phenyl-ring analogs of benztropine (BZT) substituted with 3'-, 4'-, 3',4"- and 4',4"-position Cl-groups were synthesized and their pharmacology was evaluated in order to assess more fully the contributions to pharmacological activity of substituents in these positions. METHODS: Compounds were synthesized and their pharmacological activity was assessed by examining radioligand binding and behavioral techniques. RESULTS: All of the compounds displaced [3H]WIN 35,428 binding with affinities ranging from 20 to 32.5 nM. Affinities at norepinephrine ([3H]nisoxetine) and serotonin ([3H]citalopram) transporters, respectively, ranged from 259 to 5120 and 451 to 2980 nM. Each of the compounds also inhibited [3H]pirenzepine binding to muscarinic M1 receptors, with affinities ranging from 0.98 to 47.9 nM. Cocaine and the BZT analogs produced dose-related increases in locomotor activity in mice. However, maximal effects of the BZT analogs were uniformly less than those produced by cocaine, and were obtained 2-3 h after injection compared to the relatively rapid onset (within 30 min) of cocaine effects. In rats trained to discriminate i.p. saline from 29 mumol/kg cocaine (10 mg/kg), cocaine produced a dose-related increase in responding on the cocaine lever, reaching 100% at the training dose; however, none of the BZT analogs fully substituted for cocaine, with maximum cocaine responding from 20 to 69%. Despite their reduced efficacy compared to cocaine in cocaine discrimination, none of the analogs antagonized the effects of cocaine. As has been reported previously for 4'-Cl-BZT, the cocaine discriminative-stimulus effects were shifted left-ward by co-administration of the present BZT analogs. CONCLUSIONS: The present results indicate that although the BZT analogs bind with relatively high affinity and selectivity at the dopamine transporter, their behavioral profile is distinct from that of cocaine. The present results suggest that analogs of BZT may be useful as treatments for cocaine abuse in situations in which an agonist treatment is indicated. These compounds possess features such as reduced efficacy compared to cocaine and a long duration of action that may render them particularly useful leads for the development of therapeutics for cocaine abusers.

Animals↗
PubMed2001

The role of D2-like dopamine receptors in the locomotor stimulant effects of cocaine in mice.

RATIONALE: Previous studies indicate antagonism of cocaine-stimulated locomotor activity by dopamine D2-like receptor antagonists, but only at doses of the antagonists, that by themselves attenuate locomotor activity, raising questions of the specificity of the interaction and whether it might be due solely to a summation of opposing effects. OBJECTIVES: The interactions of cocaine and several D2-like dopamine antagonists and non-dopamine "physiological antagonists" were compared across a full range of doses in order to fully characterize the interaction and assess the specificity of the effects of dopamine antagonists and cocaine. METHODS: Swiss-Webster mice were treated with either vehicle, a D2-like antagonist (haloperidol, spiperone, raclopride, spiperone, (+) or (-) eticlopride), or a "physiological" antagonist (chlordiazepoxide, clonidine, or R(-) N6-(2-phenylisopropyl)adenosine) and cocaine (5-80 mg/kg) prior to a 30-min locomotor activity test. RESULTS: All test drugs decreased locomotor activity when given alone. All test drugs attenuated cocaine-induced locomotion and decreased peak responding to cocaine. In general, the D2-like antagonists also decreased maximal responding to cocaine and decreased the slope of the ascending limb of the cocaine dose-effect curve, effects not obtained with physiological antagonists. CONCLUSIONS: Blockade of D2-like receptors resulted in an interaction with cocaine that was fundamentally different from that produced through non-dopaminergic mechanisms and appears to be more than a summation of opposing effects. The present data suggest that D2-like receptors are involved in the mechanisms underlying the induction of locomotor activity by cocaine.

Animals↗
PubMed2001

Shape and size of isolated bone mineralites measured using atomic force microscopy.

The inorganic phase of bone is comprised primarily of very small mineralites. The size and shape of these mineralites play fundamental roles in maintaining ionic homeostasis and in the biomechanical function of bone. Using atomic force microscopy, we have obtained direct three-dimensional visual evidence of the size and shape of native protein-free mineralites isolated from mature bovine bone. Approximately 98% of the mineralites are less than 2 nm thick displaying a plate-like habit. Distributions of both thickness and width show single peaks. The distribution of lengths may be multimodal with distinct peaks separated by approximately 6 nm. Application of our results is expected to be of use in the design of novel orthopaedic biomaterials. In addition, they provide more accurate inputs to molecular-scale models aimed at predicting the physiological and mechanical behavior of bone.

Animals↗
PubMed2001

Scanning acoustic microscopy study of human cortical and trabecular bone.

Scanning acoustic microscopy (SAM) has been used in the burst mode to study the properties of human cortical and trabecular bone. An Olympus UH3 SAM (Olympus Co., Tokyo, Japan) was used with a 400 MHz burst mode lens (120 degrees aperture, nominal lateral resolution 2.5 microm). The human cortical bone was from the midshaft of a femur from a 60+ male cadaver; the trabecular bone specimens were obtained from the distal femoral condyles of another 60+ human male cadaver. Elastic moduli for both trabecular and cortical bone were obtained by means of a series of calibration curves correlating SAM gray levels of known materials with their elastic moduli; specimens included: polypropylene, PMMA, Teflon, aluminum, Pyrex glass, titanium, and stainless steel. Values obtained by this method are in good agreement with those obtained by nanoindentation techniques. The three critical findings earlier by Katz and Meunier were observed here as well in both the cortical and trabecular bone samples.

Artifacts↗
PubMed2000

2D QSAR modeling and preliminary database searching for dopamine transporter inhibitors using genetic algorithm variable selection of Molconn Z descriptors.

In light of the chronic problem of abuse of the controlled substance cocaine, we have investigated novel approaches toward both understanding the activity of inhibitors of the dopamine transporter (DAT) and identifying novel inhibitors that may be of therapeutic potential. Our most recent studies toward 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, we have adapted the method of genetic algorithms-partial least squares (GA-PLS) (Cho et al. J. Comput. -Aided Mol. Des., submitted) 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, we have successfully developed a robust model of the DAT affinities of 70 structurally diverse DAT ligands. This model, with an exceptional q(2) value of 0.85, is nearly 25% more accurate in predictive value than a comparable model derived from Molconn X-derived descriptors (q(2) = 0.69). Utilizing activity-shuffling validation methods, we have demonstrated the robustness of both this DAT inhibitor model and our QSAR method. Moreover, we have extended this method to the analysis of dopamine D(1) antagonist affinity and serotonin ligand activity, illustrating the significant improvement in q(2) for a variety of data sets. Finally, we have employed our method in performing a search of the National Cancer Institute database based upon activity predictions from our DAT model. We report the preliminary results of this search, which has yielded five compounds suitable for lead development as novel DAT inhibitors.

Algorithms↗
PubMed2000

Highly selective chiral N-substituted 3alpha-[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 in the pharmacological effects of cocaine, a series of chiral and achiral N-substituted analogues of 3alpha-[bis(4'-fluorophenyl)methoxy]tropane (5) has been prepared as potential selective dopamine transporter ligands. These novel compounds displaced [(3)H]WIN 35,428 binding from the dopamine transporter in rat caudate putamen with K(i) values ranging from 13. 9 to 477 nM. Previously, it was reported that 5 demonstrated a significantly higher affinity for the dopamine transporter than the parent drug, 3alpha-(diphenylmethoxy)tropane (3; benztropine). However, 5 remained nonselective over muscarinic m(1) receptors (dopamine transporter, K(i) = 11.8 nM; m(1), K(i) = 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 analogues that retain high affinity at the dopamine transporter but have decreased affinity at muscarinic sites. Recently, it was discovered that by replacing the N-methyl group of 5 with the phenyl-n-butyl substituent (6) retention of high binding affinity at the dopamine transporter (K(i) = 8.51 nM) while decreasing affinity at muscarinic receptors (K(i) = 576 nM) was achieved, resulting in 68-fold selectivity. In the present series, a further improvement in the selectivity for the dopamine transporter was accomplished, with the chiral analogue (S)-N-(2-amino-3-methyl-n-butyl)-3alpha-[bis(4'-fluorophenyl)metho xy] tropane (10b) showing a 136-fold selectivity for the dopamine transporter versus muscarinic m(1) receptors (K(i) = 29.5 nM versus K(i) = 4020 nM, respectively). In addition, a comparative molecular field analysis (CoMFA) model was derived to correlate the binding affinities of all the N-substituted 3alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues that we have prepared with their 3D-structural features. The best model (q(2) = 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 the dopamine transporter, can now be used to design and/or predict the binding affinities of novel drugs within this class of dopamine uptake inhibitors.

Animals↗
PubMed2000

Agonist efficacy, drug dependence, and medications development: preclinical evaluation of opioid, dopaminergic, and GABAA-ergic ligands.

BACKGROUND: The general premise that receptor theory provides a useful framework for understanding the behavioral effects of psychoactive drugs has been a central tenet of behavioral pharmacology. OBJECTIVES: The purpose of this review is to reiterate this basic theme and, in particular, the proposition that current concepts of pharmacological efficacy can be effectively used to examine behavioral effects of drugs with abuse or dependence potential in a way that contributes to the discovery of drugs to treat drug dependence. EXPERIMENTAL DATA: The review begins by briefly introducing the concept of efficacy and follows with several illustrations of how our current understanding of efficacy can be used to address important research questions in drug discovery. In the first, the likelihood of developing novel opioid analgesics with reduced abuse potential is addressed by considering the different efficacy requirements for the discriminative-stimulus and antinociceptive effects of mu-opioids. From a pharmacologically different perspective within drug abuse research, the review continues with an exposition of efficacy-related differences in the behavioral effects of dopamine D1 agonists and how such differences might be exploited in different medications strategies for treating cocaine dependence. The principles of pharmacological efficacy also have come to guide the development of novel GABAA-related antianxiety medications, and this is illustrated in a discussion of the utility of low-efficacy agonists in the treatment of benzodiazepine dependence. The second half of the paper provides counterpoint to the several examples of how principles of efficacy can be applied in drug discovery. The counterpoint includes, first, a critical evaluation of how the concept of efficacy has been applied in the development of monoamine transport inhibitors as anti-cocaine medications and, in particular, the difficulties this may pose for data analysis. The review ends with a discussion of efficacy-based analysis in drug discrimination research and illustrates some of the obstacles that may be encountered in pharmacologically classifying drugs on this basis. CONCLUSIONS: Ample evidence indicates that many receptor systems can be activated in a graded manner and that principles of efficacy can be judiciously applied to understand and exploit the behavioral effects of drugs that result from such graded activation. However, as cautioned in the last sections, the misapplication of pharmacological concepts in behavioral studies of drugs may obscure their behavioral pharmacology and potentially confound drug discovery.

Animals↗
PubMed2000

3'- and 4'-chloro-substituted analogs of benztropine: intravenous self-administration and in vitro radioligand binding studies in rhesus monkeys.

RATIONALE: The reinforcing effects of many psychomotor stimulants have been related to increased dopaminergic neurotransmission. Drugs that block dopamine (DA) uptake have generally been found to function as positive reinforcers. Benztropine (BZT) and several of its halogenated analogs have previously been characterized as potent DA-uptake inhibitors with behavioral profiles that indicate diminished psychomotor stimulant effects relative to cocaine. OBJECTIVES: The present experiments were designed to examine, in rhesus monkeys, the reinforcing effects of the DA-uptake inhibitor BZT and two chloro-analogs 3'-Cl-BZT and 4'-Cl-BZT, and to compare self-administration and binding profiles. METHODS: Four rhesus monkeys self-administered cocaine i.v. under a fixed-ratio 10 (FR10) schedule until stable responding was established. Saline, and various doses of cocaine, BZT, and the BZT analogs were then made available for self-administration. Binding of these compounds to monoaminergic and cholinergic sites in monkey brain were determined using standard radioligand binding techniques. RESULTS: Self-administration was maintained by both 3'-Cl-BZT and 4'-Cl-BZT, but not by BZT. Results suggested that 3'-Cl-BZT and 4'-Cl-BZT were weak positive reinforcers. BZT and analogs bound DA transporters (DAT) with affinities higher than that of cocaine and had affinity for muscarinic binding sites. CONCLUSIONS: Surprisingly, high affinity at DATs was associated with weak or no reinforcing effects. The mechanism(s) that may underlie this dissociation between DAT actions and reinforcing effects remains to be established. These data support the proposal that a lead for the discovery of a pharmacotherapeutic agent for cocaine abuse may come from this group of compounds.

Animals↗