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L S Harris

Publications and source records attributed to L S Harris.

At least 55 records · Page 3Linked to original sources
PubMed1991

Common stereospecificity of opioid and dopamine systems for N-butyrophenone prodine-like compounds.

The two optical isomers of 1-[3-(p-fluorobenzoyl) propyl]-3-methyl-4-phenyl-4-propionoxypiperidine (FPP) were obtained by resolution of (+/-)-r-3-methyl-4-phenyl-c-4-piperidinol followed by N-alkylation and O-propionylation. These, as well as the racemate, were evaluated for their antinociceptive, opioid, and neuroleptic properties using in vivo and in vitro test systems. The results are remarkable in two respects, namely, the dextrorotatory isomer is consistently the most potent on all tests, and it acts on both opioid (mu) and neuroleptic (D2) receptors.

Alphaprodine↗
PubMed1990

Intravenous self-administration of 4-methylaminorex in primates.

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.

Animals↗
PubMed1989

Assessment of the abuse potential of acetorphan, an enkephalinase inhibitor.

The discriminative stimulus properties, reinforcing effects and physical dependence potential of acetorphan, a parenterally-active enkephalinase (E.C. 3.4.21.11) inhibitor, were assessed in the present studies. Rats trained to discriminate 2 mg/kg morphine from saline did not generalize to acetorphan at any dose tested (5-50 mg/kg). Acetorphan also had minimal reinforcing effects in rhesus monkeys. When acetorphan was substituted for cocaine, one dose (300 micrograms/kg per inj.) maintained responding somewhat above the range of vehicle values in only two of the four monkeys tested. In physical dependence studies, acetorphan also failed to produce opioid-like effects. In morphine-dependent monkeys and rats, acetorphan failed to suppress withdrawal. Additionally, there were no overt withdrawal signs observed following the termination of chronic acetorphan infusion in the rat. Together, these results indicate that acetorphan appears to have minimal abuse potential.

Animals↗
PubMed1989

Very long-acting narcotic antagonists: the 14 beta-p-substituted cinnamoylaminomorphinones and their partial mu agonist codeinone relatives.

The biological activity of 14 beta-(p-halo and p-methylcinnamoylamino)-7,8-dihydro-N-cyclopropylmethylnorcodei nones and their corresponding morphinones was investigated. In vitro, the codeinones displayed predominantly mu agonist activity in the 3H-etorphine binding assay and mouse vas deferens preparation. In vivo, in the mouse, the compounds showed weak to inactive antinociception in the tail-flick and hot-plate tets; however, they were potent agonists in the phenylquinone test and moderately weak antagonists in the tail-flick vs morphine test. They also substituted for morphine in withdrawn morphine-dependent rhesus monkeys. When given to non-withdrawn morphine-dependent monkeys, the codeinones precipitated a delayed but long-lasting withdrawal syndrome. They all generalized to codeine in the drug-discrimination test in rhesus monkeys and, in the dose range tested, two compounds were self-administered. This activity is consistent with that of a partial mu agonist. On the other hand, all the morphinones had very long-acting and highly potent mu antagonist properties. The data can be reconciled by assuming that the codeinones are partially metabolized to their respective morphinones. These compounds may be especially useful in the treatment of opioid dependence.

Analgesics↗
PubMed1987

2,5-Dimethyl-2'-hydroxy-9 alpha- and 9 beta-(3-methylbutyl)-6,7-benzomorphans and N-substituted compounds in the 9 alpha-(3-methylbutyl) series: chemistry, pharmacology, and biochemistry.

2,5-Dimethyl-2'-hydroxy-9 alpha-(3-methylbutyl)-6,7-benzomorphan, the 9 beta-analogue, and 9 alpha-N-substituted (N-ethyl, propyl, butyl, pentyl, hexyl, phenylethyl, allyl, and cyclopropylmethyl) compounds were synthesized and evaluated biochemically and pharmacologically. The 9 beta N-methyl compound was found to be as potent as morphine in the mouse hot plate assay and had one-seventh the affinity of morphine for the opioid receptor. The N-alkyl and N-phenethyl 9 alpha-substituted compounds were either inactive or relatively ineffective as antinociceptive agents. None of the examined compounds substituted for morphine in single-dose suppression studies in the rhesus monkey. The N-cyclopropylmethyl compound in the 9 alpha series had half the narcotic antagonist potency of nalorphine and one-eighth of its affinity for the opioid receptor. The 9 alpha-(3-methylbutyl) moiety, unlike bulky substituents in the 9 beta position of 6,7-benzomorphans, generally lowers affinity for the mu opioid receptor and diminishes their in vivo activity as agonists or antagonists.

Analgesics↗
PubMed1987

Synthesis and pharmacologic properties of 6-succinylcodeine.

In our search for a ligand to be used for affinity chromatography in the separation of putative, codeine-specific receptors, we have synthesized a pharmacologically active codeine derivative, 6-succinylcodeine (Ib). The structure of the compound has been confirmed. It is markedly less toxic than the parent compound, codeine (Ia), and has significantly weaker antitussive properties in the cat. On the other hand, its antinociceptive properties in the mouse and effects on guinea pig ileum are comparable to those of codeine. An interesting pharmacological property of Ib is its hypotensive effect in both cats and rhesus monkeys. The compound has been successfully coupled to an aminoalkyl agarose matrix. When coupled to the matrix, the drug loses its capacity to cause contraction of the guinea pig ileum but this property is restored upon alkaline hydrolysis of the coupled beads. Whether the diminished antitussive properties, as compared to the parent compound, or the loss of capacity to inhibit guinea pig ileum contractility when coupled to agarose would limit its usefulness for affinity chromatography of codeine-specific receptors is being investigated.

Analgesics↗
PubMed1987

Hexahydro-1H-1-pyrindines from acid rearrangement of 9-alkylidene-5-(m-methoxyphenyl)-2-methylmorphans. A new structural type of narcotic antagonists.

9-Methylene- and 9-ethylidene-5-(m-methoxyphenyl)-2-methylmorphans (1, 2) and refluxing 48% HBr have given rearrangement products 3 and 4, respectively. The structure of 4 [4a-ethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H-1- pyrindine] was determined by X-ray crystallography and that of 3 [1,4a-dimethyl-2,4a,5,6,7,7a-hexahydro-4-(3-hydroxyphenyl)-1-methyl-1H- pyrindine] follows from analogy and NMR data. Compounds 3 and 4 are opioid antagonists of about the potency of nalorphine in the tail-flick vs. morphine assay and precipitate a complete abstinence syndrome in morphine-dependent monkeys. Both are nearly devoid of antinociceptive activity and they have about 0.025 times the affinity of nalorphine for the mu opioid receptor.

Alkaloids↗
PubMed1986

Cytologic results of fine-needle aspiration biopsies of the central nervous system.

The cytologic results of 34 fine-needle aspiration (FNA) biopsies of the central nervous system (CNS) are reported. There were 31 intraoperative biopsies performed at the time of craniotomy. All the cases were diagnosed using direct smear preparations stained with Papanicolaou and Diff-Quik (Harleco, NJ) stains. The sensitivity of the procedure was 90.7%, specificity 100%, positive predictive value 100%, and efficiency of the test of 91%. There were no false-positive diagnoses and three false-negative diagnoses. This study attests to the diagnostic accuracy of FNA cytologic examination of the central nervous system. Statistical analysis of the few previous FNA biopsy series of the CNS are presented. Review of the indications, advantages and complications of CNS needle biopsy are discussed. This report supports the role of fine-needle aspiration cytology in the evaluation of CNS lesions. With recent developments in radiologic imaging, especially ultrasound and computed tomography (CT) using stereotactic guidance, specimens can be obtained for cytologic diagnosis using thinner needles. Excellent diagnostic accuracy can be obtained, as pathologists gain greater familiarity with interpreting FNA biopsy material. Other advantages of FNA biopsy of the central nervous system include the low morbidity and mortality of the procedure and the ability to perform the biopsy through a burr hole under local anesthesia and thereby decrease hospitalization time and cost.

Adult↗
PubMed1986

The role of benzodiazepine receptors in the discriminative stimulus properties of delta-9-tetrahydrocannabinol.

Twenty male Sprague-Dawley rats were trained to discriminate 3.0 mg/kg delta-9-tetrahydrocannabinol (THC) from its vehicle. Following acquisition of this discrimination animals were tested for generalization to 3.0 mg/kg diazepam. Thirteen animals showed a generalization from THC to diazepam, whereas the remaining seven animals did not. The generalization curve for diazepam was dose-dependent from 0.1 to 10.0 mg/kg in the first group; the latter group showed no generalization from THC at any dose of diazepam in this range. No differences were found between these groups in the generalization curve for THC. The benzodiazepine antagonist Ro 15-1788 (2.0 mg/kg) antagonized the generalization to diazepam in the group that discriminated diazepam as THC. In contrast, Ro 15-1788 increased THC lever responding of 10 mg/kg diazepam in the group which did not generalize from THC. Ro 15-1788 did not alter the discriminability of THC in either group. THC also showed partial generalization to pentobarbital (1 to 10 mg/kg). The generalization was again complete in one subgroup and absent in another, but there was only a 43 percent overlap between the subgroups found with testing for generalization to diazepam. The percent THC lever responding with 3.0 mg/kg pentobarbital was increased by Ro 15-1788 in the group which generalized to diazepam, but not the other group. These data suggest that the discriminative stimulus properties of THC may have some commonality with the effects of diazepam in a subpopulation of rats trained to discriminate THC. These THC-like effects of diazepam are probably mediated by benzodiazepine receptors since they are antagonized by a specific benzodiazepine receptor antagonist.

Animals↗
PubMed1986

The stimulants and hallucinogens under consideration: a brief overview of their chemistry and pharmacology.

The substances under review are a heterogeneous set of compounds from a pharmacological point of view, though many have a common phenylethylamine structure. Variations in structure lead to marked changes in potency and characteristic action. The introductory material presented here is meant to provide a set of chemical and pharmacological highlights of the 28 substances under consideration. The most commonly used names or INN names, Chemical Abstract (CA) names and numbers, and elemental formulae are provided in the accompanying figures. This provides both some basic information on the substances and a starting point for the more detailed information that follows in the individual papers by contributors to the symposium.

Animals↗
PubMed1986

Self-administration of methylenedioxymethamphetamine (MDMA) by rhesus monkeys.

Four rhesus monkeys trained to press levers for intravenous cocaine infusions were tested with saline and (+/-)-3,4-methylenedioxymethamphetamine (MDMA; 3-300 micrograms/kg per infusion) during daily 1-h sessions. From four to over nine times more cocaine infusions were obtained than saline infusions during baseline sessions. When MDMA was substituted for cocaine, at least one dose was self-administered in 3 of the 4 monkeys at rates that exceeded the range of saline infusions. In fact, two of the monkeys self-administered a dose of MDMA at a greater rate than cocaine. These results demonstrate that MDMA can serve as a positive reinforcer for rhesus monkeys and, taken together with other preclinical behavioral studies, suggest a potential for recreational use of MDMA by humans.

3,4-Methylenedioxyamphetamine↗
PubMed1986

Probes for narcotic receptor mediated phenomena. 13. Potential irreversible narcotic antagonist-based ligands derived from 6,14-endo-ethenotetrahydronororipavine with 7-(methoxyfumaroyl)amino, (bromoacetyl)amino, or isothiocyanate electrophiles: chemistry, biochemistry, and pharmacology.

N-Allyl-, N-(cyclopropylmethyl)-, and N-propyl-endo-ethenotetrahydronororipavines (N-substituted 6,14-endo-etheno-4,5-epoxy-3-hydroxy-6-methoxymorphinans) were synthesized with potential acylating or alkylating moieties at the C-7 position (isothiocyanato, (bromoacetyl)amino, and (methoxyfumaroyl)amino) and examined in vivo for their narcotic agonist and antagonist activities and for their ability to interact with opioid receptors in vitro. The N-(cyclopropylmethyl)-substituted compounds were found to have the highest affinity for opioid receptors among these N-substituted compounds, although all of them were found to be reasonably potent narcotic antagonists in the mouse tail flick vs. morphine assay. Their in vivo potency ranged from 1/8 to 4 times that of nalorphine on intravenous injection in mice. Rat brain membrane binding studies indicated that the compounds interacted with opioid receptors with potencies that ranged from 0.5 times that of morphine (8c, 9c, and 10c) to 0.017 that of morphine (8b). Among the compounds studied here, only the previously reported isothiocyanato compound (10c) and (methoxyfumaroyl)amino compound (8c) interacted irreversibly and selectively with mu or delta opioid receptors, respectively, in assays using NG108-15 neuroblastoma-glioma hybrid cells and/or in a rat brain membrane preparation. Both 8c and 10c were found to interact irreversibly, to a limited extent, with kappa opioid sites in rat brain membranes in which the mu and delta opioid receptors were depleted by interaction with the mu-selective irreversible ligand BIT and the delta-selective irreversible ligand FIT. Neither compound showed irreversible actions in the electrically stimulated mouse vas deferens preparation.

Animals↗
PubMed1986

Dependence on tetrahydrocannabinol in rhesus monkeys.

The present studies examined whether dependence could be induced by continuous infusion of delta-9-tetrahydrocannabinol (THC), as evidenced by behavioral disruptions during withdrawal of THC administration. Four rhesus monkeys lever pressed under fixed-ratio schedules for their daily food rations during four, daily, 0.5 -hr sessions. Initially, the monkeys were tested before, during and after continuous i.v. infusions of THC. A dosage regimen of 0.05 mg/kg/hr for 10 days for three of the monkeys and a somewhat greater regimen in the fourth had little direct effect on rates of respondings for food during THC infusion, but marked decreases in response rates occurred in each monkey during withdrawal. These effects generally did not occur until the second day of withdrawal, and often lasted for over a week. These initial demonstrations were replicated subsequently with lower solvent concentrations. In the final study, THC was administered for a greater number of days and at higher dosages than during any of the previous studies. Response rate reductions again occurred within 2 to 3 days of withdrawal. When THC was readministered, reversal of the withdrawal effects occurred in that withdrawal-induced rate decreases were halted and rates increased subsequently. Administration of THC was discontinued after 2 to 3 days of its readministration. Response rates again decreased within the first 3 days after this withdrawal and then recovered slowly with time. Withdrawal of THC administration can disrupt operant behavior, and these disruptions can be reversed by resumption of THC administration, indicating that dependence upon this drug can be produced in rhesus monkeys.

Animals↗