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Biomedical subjects

A E Jacobson

Publications and source records attributed to A E Jacobson.

At least 163 records · Page 9Linked to original sources
PubMed1985

Effects of metaphit, a proposed phencyclidine receptor acylator, on catalepsy in pigeons.

Metaphit, a derivative of phencyclidine (PCP), irreversibly binds to PCP sites in rat brain homogenates. PCP-induced catalepsy in pigeons, which is a pharmacologically specific and stereoselective phenomenon, was used to study pharmacological consequences of the proposed covalent bonding of metaphit to PCP sites. Metaphit pretreatment increased the cataleptic effects induced by cumulative doses of PCP-type drugs (i.e., PCP, ketamine and m-amino PCP) and of drugs that have PCP-like actions (i.e., dexoxadrol, LY 154716 and cyclazocine). Metaphit did not affect pentobarbital-induced loss of righting, head-drop and eye closure. Metaphit itself induced a PCP-like catalepsy. Isobolographic analysis of the interactions between metaphit and PCP-like drugs suggested that metaphit potentiated the catalepsy-inducing effects of these drugs. The possibility that metaphit exerts its potentiating effects by inhibition of PCP biotransformation was evaluated by measuring plasma and brain concentrations of PCP after pretreatment with either metaphit or SKF-525A, an inhibitor of the enzyme systems involved in PCP biotransformation. SKF-525A, but not metaphit, increased brain levels of PCP. The results suggest that metaphit acts not as an antagonist of PCP but as a less-potent, long-acting, specific PCP-like agonist. Potentiation by metaphit of the cataleptic effects of chemically diverse drugs with PCP-like actions does not appear to be based on inhibition of the enzyme systems involved in metabolism of those drugs.

Acylation↗
PubMed1984

Phencyclidine-induced catalepsy in pigeons: specificity and stereoselectivity.

A procedure is described for the rapid assessment of cataleptic activity (loss of righting, without head-drop and without eye closure) of phencyclidine-type drugs. Single- and cumulative-dosing procedures with phencyclidine and ketamine produced similar results. Pentobarbital produced loss of righting at doses which also induced head-drop and eye closure. Catalepsy was induced exclusively by the d-isomers of ketamine, 1-(1-phenylcyclohexyl)-3-methylpiperidine and alpha-dioxadrol. The procedure is suitable for studying compounds which may interact with phencyclidine receptors.

Animals↗
PubMed1984

Agonist-antagonist actions and stereoselectivity of optical pairs of some N-substituted alpha-N-normetazocines.

alpha-(-)-, (+)-, and (+/-)-N-4-Methylpentyl-, (-)- and (+)-N-cis-3-chloroallyl-, and (-)- and (+)-N-propynyl-N-normetazocine (I, II, and III, respectively) have been prepared from alpha-(-)-, (+)-, and (+/-)-N-normetazocine (IV) and tested for antinociceptive activity in mice and in morphine-dependent rhesus monkeys. The results obtained with Ia and b somewhat resemble the results obtained with the corresponding phenazocine isomers, whereas those observed with IIa and b more nearly correspond with those reported for (+)- and (-)-N-allyl-N-normetazocine (SKF 10,047; NANM). The propynyl isomers (IIIa and b) display profiles of activity more closely like the corresponding isomers of metazocine. Evidence is considered which suggests that some of the (+)-isomers merit closer scrutiny in animal and human studies.

Analgesics↗
PubMed1984

9 alpha- and 9 beta-Hydroxyphenylmorphans.

Platinum-oxide hydrogenation of 5-m-methoxyphenyl-2-methyl-9-oxomorphan (I) gave the 9 alpha-hydroxy racemate (II) whose phenolic analogue (III) is a strong antinociceptive agent, fully supportive of morphine dependence in rhesus monkeys. The di-O-acetyl derivative (VI) of III was similar to III in its profile of activity. The diastereoisomer of III (VII), obtained by hydrogenation of the methobromide of I (IV), extrusion of methyl bromide, and O-demethylation of the resultant free base (VIII), was almost inactive antinociceptively and did not suppress withdrawal symptoms in morphine-dependent monkeys. The orientation of the C-9 hydroxyl groups was deduced from spectral data and by analogy.

Analgesics↗
PubMed1984

Tritiated-6-beta-fluoro-6-desoxy-oxymorphone: a highly selective ligand for the opiate mu receptor whose binding is characterized by low nonspecific binding.

In this paper we examine the binding of [3H]FOXY (tritiated-6-beta-fluoro-6-desoxy-oxymorphone) to membranes of rat brain. Using the site-directed alkylating agents BIT and FIT, evidence is presented that [3H]FOXY selectively labels mu opiate binding sites in vitro. Further, BIT and FIT did not significantly affect [3H]bremazocine binding to kappa receptors. Scatchard plots of [3H]FOXY binding were somewhat curvilinear, suggesting the presence of two classes of mu binding sites. At concentrations up to 19 nM, 90 percent of the total binding was specific. The combination of high mu-selectivity and low nonspecific binding suggests the [3H]FOXY may prove to be a powerful tool for studying the opiate mu receptor.

Animals↗
PubMed1984

Probes for narcotic receptor mediated phenomena. 10. Irreversible ligands to opioid receptors based on biologically potent endoethenooripavines. Reversible binding of fit to mu and delta opioid receptors.

A p-isothiocyanatophenylacetylamino moiety at the C7alpha position on an endoethenooripavine (NIH 10358) was found to irreversibly bind to both the mu and delta opioid receptors in rat brain membrane preparations. However, the same endoethenooripavine nucleus with a p-methylfumaroylaminophenylacetylamino moiety at that position (NIH 10364) binds specifically and irreversibly to only mu opioid receptors. Hypotheses are being developed concerning receptor subclass alkylation specificity. For example, it has now been found that the delta receptor irreversible agonist, FIT, can interact with both mu and delta receptors in a reversible manner.

Alkylating Agents↗
PubMed1984

Preparation of rat brain membranes greatly enriched with either type-I-delta or type-II-delta opiate binding sites using site directed alkylating agents: evidence for a two-site allosteric model.

Although it is widely accepted that radiolabeled prototypic delta receptor agonists label two binding sites in vitro, the mechanism by which mu ligands inhibit peptide binding as well as the identity of the binding sites remains unsettled (Rothman and Westfall, Mol. Pharmacol. 21:538-547, 1982 ; Bowen et al., Proc. Natl. Acad. Sci. U.S.A. 78:4818-4822, 1981). Using the site directed, receptor selective alkylating agents, BIT and FIT (Rice et al., Science 220:314-316, 1983), we describe the preparation of membranes devoid of high affinity binding sites and demonstrate that the mu agonist oxymorphone noncompetitively inhibits the binding of [3H]DADL to the residual lower affinity binding sites.

Alkylating Agents↗
PubMed1984

Morphine noncompetitively inhibits [3H]leucine enkephalin binding to membranes lacking type-II delta binding sites: evidence for a two-site allosteric model.

Using the site-directed, delta-selective alkylating agent FIT (Rice et al., Science 220, 314-316, 1983), membranes devoid of detectable higher affinity delta binding sites were prepared. As compared to control membranes, the IC50 of morphine required to inhibit [3H]LE binding to FIT-treated membranes was two orders of magnitude lower. Further, morphine was a noncompetitive inhibitor of [3H]LE binding to FIT-treated membranes, supporting the notion that the lower affinity delta binding site is the delta binding site of the opiate receptor complex.

Allosteric Regulation↗
PubMed1984

Ionic conditions differentially affect 3H-DADL binding to type-I and type-II opiate delta receptors in vitro.

It is widely accepted that the prototypic delta agonist DADL (D-ala2-D-leu5-enkephalin) labels two binding sites in vitro. Using the site directed, receptor selective alkylating agents, BIT and FIT (Rice et al.. Science 220:314-316, 1983), we recently described (Rothman et al, Neuropeptides, in press) the preparation of membranes possessing only lower affinity 3H-DADL binding sites (FIT-treated membranes, type-I delta sites) as well as membranes greatly enriched with higher affinity binding sites (BIT-treated membranes, type-II delta sites). In this paper we report that ionic conditions differentially affect the binding of 3H-DADL to FIT- and BIT-treated membranes, supporting the notion that 3-H-DADL labels two distinct delta binding sites.

Animals↗
PubMed1984

Probes for narcotic receptor mediated phenomena. 7. Synthesis and pharmacological properties of irreversible ligands specific for mu or delta opiate receptors.

Syntheses of affinity reagents for opiate receptors based on the fentanyl, endo-ethenotetrahydrooripavine, and etonitazene carbon-nitrogen skeletons are described. The isothiocyanate, bromoacetamido, and methylfumaramido alkylating functions were employed in these compounds, some of which had previously been shown to be mu specific (12, BIT) and delta specific (8, FIT and 19, FAO) in vitro. Antinociceptive activity of the title compounds was determined in the mouse hot-plate test, which revealed that certain compounds in each class showed morphine-like activity. The binding EC50 values against [3H]Dalamid for opiate receptors in NG108-15 (delta receptors) and rat brain membranes (mu + delta receptors) are also reported. With this type of experiment, it was possible to independently measure the apparent affinity of the etonitazene congeners 12-14 for the mu and delta receptors.

Animals↗
PubMed1984

Synthesis and biological evaluation of 14-alkoxymorphinans. 1. Highly potent opioid agonists in the series of (-)-14-methoxy-N-methylmorphinan-6-ones.

A series of eight (-)-14-methoxymorphinan-6-ones was synthesized and biologically evaluated. The morphinanones 3-7 were prepared from 3-desoxy-7,8-dihydro-14-hydroxymorphinone (1). The key step in this synthetic sequence, O-methylation in position 14, was accomplished with dimethyl sulfate. Hydrolysis followed by reductive opening of the 4,5-oxygen bridge afforded the phenol 4, which was O-methylated to give 5. Removal of the 4-OH group yielded the aromatic unsubstituted morphinan 7. The synthesis of 9 and 10 was accomplished by starting from 14-methoxy-7,8-dihydrocodeinone and involved a similar reaction sequence. The compounds 12-15 were synthesized from oxymorphone (11), which was 3-O-benzylated, 6,14-bis-O-methylated with dimethyl sulfate, hydrolyzed, and hydrogenated to yield the oxymorphone 14-O-methyl ether 15. The derivatives 3, 4, 5, 7, 9, 10, 14, and 15 exhibited high antinociceptive potency in the hot-plate assay in mice, after both subcutaneous and oral administration. The most potent derivative in this series (15) showed a potency (sc) about 400 times higher than that of morphine and about 40 times higher than its 14-OH analogue oxymorphone (11). The 14-OCH3 series also exhibited a considerably higher affinity to opioid receptors in binding studies using [3H]naloxone as ligand when compared to their 14-OH analogues.

Analgesia↗
PubMed1984

Discriminative stimulus effects of reversible and irreversible opiate agonists: morphine, oxymorphazone and buprenorphine.

Pigeons were trained under a multiple-trial procedure to discriminate morphine (5.6 mg/kg) from saline. Morphine, oxymorphazone and buprenorphine each occasioned complete drug-appropriate responding in a dose-related manner and, at larger doses, suppressed responding completely. The order of potency as discriminative stimuli was buprenorphine greater than oxymorphazone greater than morphine; the potencies in suppressing responding were oxymorphazone greater than morphine greater than buprenorphine. Pretreatment with naltrexone (0.01-1.0 mg/kg) shifted the discrimination dose-effect curves to the right for all three compounds. When a discriminative effect was first established with morphine or oxymorphazone, the subsequent administration of naltrexone (0.01-0.32 mg/kg) completely and dose dependently antagonized the cue produced by each. Thus, oxymorphazone was not markedly different from morphine in its profile of action. Naltrexone up to 10.0 mg/kg failed to reverse completely the established discriminative effects of 0.32 mg/kg of buprenorphine, indicating that buprenorphine acts as an irreversible, morphine-like agonist in this behavioral situation. Buprenorphine had a much longer duration of action (3-4 days) than morphine (24 hr) or oxymorphazone (24-48 hr). Neither prolonged exposure to buprenorphine nor treatment with 100.0 mg/kg/day of morphine for 5 days produced tolerance to the discriminative or rate-suppressing effects of morphine. Buprenorphine also failed to antagonize either the discriminative or rate-suppressing effects of morphine. These data clearly demonstrate the irreversible morphine-like discriminative effects of buprenorphine and the reversible actions of morphine and oxymorphazone. These results also indicate that drug discrimination procedures may be valuable for the identification and characterization of irreversible agonists and antagonists.

Animals↗