Search PubMed⌕ Search

Biomedical subjects

A E Jacobson

Publications and source records attributed to A E Jacobson.

At least 127 records · Page 7Linked to original sources
PubMed1987

Distribution of opiate receptor subtypes and enkephalin and dynorphin immunoreactivity in the hippocampus of squirrel, guinea pig, rat, and hamster.

The distribution of enkephalin and dynorphin immunoreactivity in the hippocampus of four rodent species (gray squirrel, guinea pig, rat, and hamster) is compared with the pattern of opiate receptor subtypes (mu, delta, and kappa). The distribution of opioid peptides is fairly consistent in the anterior hippocampus of these four species. Intense immunoreactivity for dynorphin and enkephalin is found in the hilus of the dentate gyrus and in the mossy fiber system. Occasional immunoreactive processes are seen in the dentate molecular layer and scattered throughout the CA1 and CA3 fields. In the rat and hamster, an additional plexus of enkephalinergic fibers straddles both sides of the hippocampal fissure. Cells immunoreactive for both opioid peptides are located in and just superficial to the dentate granule cell layer. Opiate receptors are variably distributed in these rodent species. In the squirrel, guinea pig, and hamster, mu and kappa binding is dense in the stratum lucidum of CA3 and the molecular layer of the dentate gyrus. In the rat, dense mu and kappa binding is localized within and adjacent to the pyramidal and granule cell layers. Delta receptor patterns show additional species differences. In the rat, the delta distribution is similar to the mu and kappa patterns. In the other species, the delta binding pattern is generally the inverse of the mu/kappa pattern: most areas of the hippocampus are enriched in delta sites, whereas the stratum lucidum and the pyramidal cell layer are receptor-sparse. Thus, the stratum lucidum--site of dense terminations of mossy fibers containing opioid peptides--is characterized by selectively sparse delta receptors in four species and by selectively dense kappa receptors in three species. The three receptor subtypes, taken either individually or together and compared to the peptides, are more variably and more widely distributed throughout the hippocampus and fail to show a correspondence with opioid-peptide-containing terminals. The mismatches suggest that receptor locations and densities are organized without relation to the sites of relevant transmitter release.

Animals↗
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

Phencyclidine (PCP)-like discriminative stimulus effects of metaphit and of 2-amino-5-phosphonovalerate in pigeons: generality across different training doses of PCP.

Pigeons were trained to discriminate either a fixed dose of PCP (1 mg/kg; n = 3) or a progressively decreasing dose (1-0.56-0.32 mg/kg; n = 4) from saline. Lowering of the training dose shifted the dose-effect curve for PCP's discriminative stimulus effects about 5-fold to the left, in a parallel manner, but did not decrease the accuracy of the discrimination performance and did not significantly increase the extent to which pentobarbital and chlordiazepoxide produced PCP-appropriate responding. Dose-effect curves based on binary generalization data were evaluated statistically with new methods that may be more appropriate than those used previously. Metaphit, a proposed PCP-receptor acylator, and 2-amino-5-phosphonovalerate (AP5), an N-methyl-D-aspartate (NMDA) antagonist, produced complete PCP-appropriate responding in the high training dose group only at doses that suppressed the rate of responding and that produced ataxia. However, 4-fold lower doses of metaphit and AP5, which did not produce directly observable behavioral effects, were found to substitute completely for PCP in the low training dose group. These data support the notion that PCP, metaphit, and AP5 have a common discriminative effect in pigeons.

2-Amino-5-phosphonovalerate↗
PubMed1987

Excitatory amino acid antagonists induce a phencyclidine-like catalepsy in pigeons: structure-activity studies.

The excitatory amino acid antagonists D,L-2-amino-5-phosphonovalerate (D,L-AP5), its isomers D-(-)-AP5 and L-(+)-AP5, D,L-2-amino-4-phosphonobutyrate (AP4), D,L-2-amino-7-phosphonoheptanoate (AP7), beta-D-aspartylaminomethylphosphonic acid (ASP-AMP), cis-2,3-piperidinedicarboxylic acid (cis-PDA), and gamma-D-glutamylaminomethylsulphonic acid (GAMS) were tested for their ability to produce a phencyclidine (PCP)-like catalepsy in pigeons when administered intracerebroventricularly. Each of the antagonists produced catalepsy, although L-AP5, and the non-selective antagonists GAMS and cis-PDA, produced the effect only at toxic doses. The rank order of potency to produce catalepsy was AP7 greater than D-AP5 greater than D,L-AP5 greater than cis-PDA greater than ASP-AMP greater than AP4 greater than L-AP5 greater than GAMS; there was a strong positive correlation between this rank order of potency in vivo and the potency order of these compounds in vitro as NMDA antagonists. The antagonists did not displace significant amounts of [3H]N-[1-(2-thienyl)cyclohexyl]piperidine (a congener of phencyclidine) from its recognition site in the brain of pigeon. Thus, the PCP-like catalepsy that is produced by the excitatory neurotransmission at NMDA-preferring receptors that are distinct from, but related to, PCP receptors. The results strongly support the hypothesis that a reduction of neurotransmission at excitatory synapses, utilizing NMDA-preferring receptors, may underlie catalepsy in pigeons induced by PCP.

Amino Acids↗
PubMed1987

Intracerebroventricular administration of superFIT and its enantiomer to rats: evidence for in vivo acylation of [3H]DADL binding sites.

SuperFIT is an high affinity acylating ligand derived from fentanyl. Previous studies suggested that a selective acylation of delta receptors (J. Med. Chem. 29:1087-1093, 1986) resulted from exposure of membranes to this and structurally related compounds. We report in this preliminary study that intracerebroventricular administration of either superFIT or its enantiomer 18 to 24 hours prior to sacrifice decreased the subsequent binding of [3H]DADL to both its higher and lower affinity binding sites.

Acylation↗
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↗
PubMed1987

Metaphit irreversibly inhibits [3H]threo-(+/-)-methylphenidate binding to rat striatal tissue.

Metaphit (1-[1-(3-isothiocyanatophenyl)cyclohexyl]-piperidine), a derivative of phencyclidine that contains an isothiocyanate group on the meta position of the aromatic ring, resembles its parent compound (phencyclidine) in its ability to inhibit the binding of the stimulant drug [3H]threo-(+/-)-methylphenidate to crude synaptosomal membranes from rat striatal tissue (IC50 = 1.4 and 6.2 microM for phencyclidine and Metaphit, respectively). Unlike phencyclidine, however, Metaphit appears to inhibit binding of the radiolabeled stimulant in an irreversible manner, as the degree of inhibition of binding of the stimulant does not diminish when the Metaphit-treated tissue is subjected to repeated washings before determination of the binding of [3H]threo-(+/-)-methylphenidate. This finding suggests that Metaphit may be a useful tool in the study of the molecular basis of stimulant action.

Animals↗
PubMed1987

Enantiomeric and diastereomeric dioxadrols: behavioral, biochemical and chemical determination of the configuration necessary for phencyclidine-like properties.

Dioxadrol exists in four isomeric forms. alpha-(+)-Dioxadrol (dexoxadrol) showed phencyclidine (PCP)-like activity in rhesus monkeys trained to discriminate s.c. administration of ketamine, but neither alpha-(-)-dioxadrol (levoxadrol) nor beta-(+/-)-dioxadrol showed such activity. In addition, response-contingent i.v. dexoxadrol maintained higher rates of responding than either levoxadrol or beta-dioxadrol in monkeys experienced with ketamine self-administration. The order of potency in displacing bound 1-[1-(2-thienyl)cyclohexyl]piperidine from binding sites in rat brain homogenates was dexoxadrol much greater than levoxadrol = beta-(+/-)-dioxadrol. Viewed in the context of previous studies with stereochemical probes of the PCP receptor, these results extend and confirm the supposition that dexoxadrol and levoxadrol are the stereochemical probes of choice in the study of effects mediated through PCP receptors. The absolute configuration of dexoxadrol was determined to be 4S, 6S by X-ray crystallography, thus defining the optimum chirality necessary for receptor binding and PCP-like activity in the dioxadrol series. Based on these and other considerations, receptor-active conformations of dexoxadrol and PCP are proposed.

Analgesics↗
PubMed1986

Opiate receptors in rat pituitary are confined to the neural lobe and are exclusively kappa.

The distribution and density of opiate receptor subtypes in rat pituitary were examined by quantitative autoradiography of tritiated ligand-binding to slide-mounted sections under conditions optimized to label mu, delta, or kappa opiate receptors. Mu and delta receptor-binding was virtually undetectable in the pituitary. Kappa receptor-binding was confined to the neural lobe where it was densest in the external rim. Autoradiographic silver grains in emulsion-coated, Nissl-stained sections were preferentially located between cells, suggesting kappa receptor localization on nerve terminals and/or processes of pituicytes.

Animals↗
PubMed1986

Is Metaphit a phencyclidine antagonist? Studies with ketamine, phencyclidine and N-methylaspartate.

The dissociative anaesthetics, phencyclidine and ketamine, block excitation of central neurones by N-methylaspartate. Using the technique of microelectrophoresis on rat spinal neurones in vivo Metaphit, a phencyclidine receptor acylating agent, was tested to see whether it would antagonise this effect of dissociative anaesthetics. The predominant effect of Metaphit was, however, to reduce N-methylaspartate induced excitation. It is concluded that Metaphit has mixed agonist/antagonist effects at the phencyclidine receptor.

Action Potentials↗
PubMed1986

Morphine tolerance increases mu-noncompetitive delta binding sites.

In light of more recent knowledge concerning endogenous opioid peptides and their multiple opiate receptors, we reevaluated the effects of morphine tolerance on opiate receptor binding parameters. Rats were implanted with morphine or placebo pellets, and [3H][D-Ala2,D-Leu5]enkephalin ([3H]DADL) was used to label brain membranes. Utilizing the technique of binding surface analysis, we observed a selective 47% up-regulation of lower affinity [3H]DADL binding sites (mu-noncompetitive delta binding sites) in morphine pelleted rats. To corroborate these results, we treated brain membranes with the site directed alkylating agent FIT (N-phenyl-N-[1-(2-p-isothiocyanato)phenyl-ethyl)-4-piperidinyl] propanamide), which results in membranes highly enriched with the lower affinity [3H]DADL binding site. Scatchard plots of [3H]DADL binding to FIT-treated membranes also revealed that chronic morphine treatment produced a 60-65% up-regulation of the mu-noncompetitive delta binding site. These data indicate that chronic morphine alters a selective subpopulation of opiate receptors that may play a role in the mechanisms of opiate tolerance and physical dependence.

Animals↗
PubMed1986

Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions.

The interaction of phencyclidine, dexoxadrol, their analogs and stereoisomers with phencyclidine receptors was compared to their ability to induce stereotyped behavior and ataxia after i.c.v. administration to rats. The order of potency for binding to phencyclidine receptors revealed that among the stereoisomers of phencyclidine derivatives, the (+) isomer was more potent than the (-) isomer. A similar order of potency of phencyclidine derivatives and degree of stereoselectivity was seen in the assays for stereotyped behavior and phencyclidine receptor interactions, which resulted in a good correlation between the relative potencies for binding to phencyclidine receptors and inducing stereotyped behavior. However, the order of potency for induction of ataxia and the stereoselectivity was different than that seen in the assays for phencyclidine receptor interactions and stereotyped behavior. A comparison of relative potencies for binding to phencyclidine receptors to induction of ataxia still resulted in a good fit to a straight line, but the line did not intersect the origin, indicating that a non-phencyclidine receptor component is also involved in mediating ataxia. Dextrorphan and 2-methyl-3,3-diphenyl-3-propylamine were equipotent as phencyclidine in phencyclidine receptor and behavioral assays. The order of potency for interacting with phencyclidine receptors and inducing phencyclidine-like behavior by the isomers of cyclazocine were opposite to that of other phencyclidine analogs. Also, the order of potency for induction of ataxia by the isomers of N-allylnormetazocine was opposite to that for phencyclidine receptor interactions. Ethylketocyclazocine did not induce any stereotyped behavior or ataxia, indicating that it is unlikely that a kappa opioid receptor interaction plays a role in mediating ataxia. Furthermore, stereotyped behavior and ataxia were not due to interactions with mu, kappa or delta opioid receptors as naloxone did not antagonize the behavioral effects of phencyclidine, (-)cyclazocine or (-)N-allylnormetazocine. These results indicate that stereotyped behavior is mediated by phencyclidine receptors, whereas ataxia is mediated by more than just phencyclidine receptors.

Animals↗
PubMed1986

Interactions of phencyclidine with hippocampal circuitry: evidence for neuronal heterogeneity.

The discovery of phencyclidine (PCP) receptors has stimulated the search for specific PCP antagonists. A direct product of this research is metaphit, an irreversible PCP ligand, which has recently been synthesized. In this study we examined the effects of metaphit on the responses of hippocampal neurons to PCP. On the basis of unfiltered action potential durations, hippocampal cells were divided into two groups, complex-spike cells and theta neurons. Local application of PCP caused inhibitions of the spontaneous firing rates of complex-spike cells. Metaphit, locally applied, antagonized approximately 50% of these responses, while the remaining responses were unaffected. In contrast, PCP caused increases in the spontaneous firing rates of theta cells and in almost all cases, these responses to PCP were attenuated by metaphit administration. These effects of metaphit were specific for PCP as the responses to locally applied norepinephrine were not altered by metaphit. The data suggest two mechanisms of action of PCP in the hippocampus. In addition, these mechanisms may be localized in part to different cell types.

Action Potentials↗
PubMed1986

Probes for narcotic receptor mediated phenomena. 9. Synthesis of (+/-)-(3 alpha,6a alpha,11a beta)-1,3,4,5,6,11a-hexahydro-2-methyl-2H-3,6a- methanobenzofuro[2,3-c]azocin-10-ol, an oxide-bridged 5-(m-hydroxyphenyl)morphan.

The synthesis of racemic (3 alpha,6a alpha,11a beta)-1,3,4,5,6,11a- hexahydro-2-methyl-2H-3,6a-methanobenzofuro[2,3-c]azocin -10-ol (2d) is described. The route used acid-catalyzed ring closure of enamine 5 to yield the unsaturated phenylmorphan 6. Conversion of 6 to oxide-bridged 2d was accomplished in a multistep fashion that utilized the introduction of a bromine atom, followed by O-demethylation of the phenolic methyl ethers and base-catalyzed intramolecular phenoxide displacement of the bromine. Compound (+/-)-2d represents an oxide-bridged derivative of the potent 5-(m-hydroxyphenyl)morphan class of opioid analgesics 1. Unlike the 5-(m-hydroxyphenyl)morphans that have a freely rotating phenyl group, 2d has the phenyl ring conformationally restricted at an angle of 49 degrees relative to atoms 1, 3, 11a, and 12 of 2d. The low binding of (+/-)-2d to rat brain homogenate receptor preparations [IC50 = 1000 nM] may indicate that the phenyl angle of 49 degrees is not suitable for binding to opioid receptors.

Animals↗
PubMed1986

Probes for narcotic receptor mediated phenomena. 12. cis-(+)-3-Methylfentanyl isothiocyanate, a potent site-directed acylating agent for delta opioid receptors. Synthesis, absolute configuration, and receptor enantioselectivity.

The first enantiomeric pair of irreversible opioid ligands [(+)- and (-)-4] were synthesized in greater than 99.6% optical purity as determined by HPLC analysis of diastereoisomeric derivatives of the intermediate 3-methyl-N-phenyl-4-piperidinamine enantiomers. Single-crystal X-ray analysis of the (R,R)-L-(+)-tartaric acid salt of (-)-9 revealed the absolute configuration to be 3S,4R. The absolute configuration of (-)-3 [cis-(-)-3-methylfentanyl] and (-)-4 derived from (-)-9 is thus 3S,4R and that of (+)-3 and (+)-4 is 3R,4S. The (+) enantiomer of 4 (SUPERFIT) was shown to be highly potent and specific for acylation of delta opioid receptors (to the exclusion of mu) in rat brain membranes like its achiral prototype FIT and was about 10 times as potent as the latter in this assay. The (+)-4 was about 5 times as potent as FIT in acylation of delta receptors in NG108-15 neuroblastoma X glioma hybrid cells and about 50 times as potent as its enantiomer. Both FIT and (+)-4 behaved as partial agonists in inhibition of delta receptor coupled adenylate cyclase in NG108-15 membranes and (+)-4 was 5-10 times more potent than FIT and about 100 times more potent than its enantiomer in this assay. Dibromination of amine 12, catalytic exchange of bromine with tritium gas, and reaction of the labeled amine with thiophosgene afforded [3H]-(+)-4 with a specific activity of 13 Ci/mmol. Previous experiments indicated (+)-4 acylates the same 58 000-dalton glycoprotein previously shown to be acylated by FIT but with less nonspecific labeling. In view of the high potency and specificity of (+)-4 and the availability of its enantiomer, it seems likely that these compounds will prove to be valuable tools for study of the opioid receptor complex.

Acylation↗
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

Comparison of (-)-eseroline with (+)-eseroline and dihydroseco analogues in antinociceptive assays: confirmation of rubreserine structure by X-ray analysis.

The enantiomers of eseroline bind to opiate receptors of rat brain membranes with equal affinities and show opiate agonist properties as inhibitors of adenylate cyclase in vitro. However, only (-)-eseroline shows potent narcotic agonist activity in vivo, similar to that of morphine. Neither (-)-noreseroline, (+)-eseroline, nor the open dihydroseco analogue (-)-8 shows analgetic effects in vivo. The structure of rubreserine being a resonance hybrid of an o-quinone with its zwitterionic mesomer is confirmed by solid-state X-ray diffraction analysis.

Adenylyl Cyclase Inhibitors↗