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At least 1,513 records · Page 84Linked to original sources
PubMed1982

Aminotetralins as narcotic antagonists. 2. Synthesis and opiate-related activity of 1-phenyl-3-aminotetralins.

The synthesis and analgetic agonist and antagonist activities of several 3-[N-(cyclopropylmethyl)-N-methylamino]-1-phenyltetralins are reported. The design of these agents was based partially on the possibility of two aryl receptor binding sites on the opiate receptor. The agents lack the phenolic hydroxyl and quaternary carbon functionalities generally associated with opiate activity; yet both the cis- and trans-1-phenyl-3-aminotetralins displayed significant agonist and antagonist activity. In preliminary studies, the trans isomer neither suppressed nor precipitated withdrawal signs in addicted monkeys.

Analgesics, Opioid↗
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↗
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↗
PubMed1997

Probes for narcotic receptor-mediated phenomena. 25. Synthesis and evaluation of N-alkyl-substituted (alpha-piperazinylbenzyl)benzamides as novel, highly selective delta opioid receptor agonists.

A series of N-alkyl- and N,N-dialkyl-4-[alpha-[(2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl] benzyl]-benzamides were synthesized and evaluated for binding affinities at mu, delta, and kappa opioid receptor subtypes. Several compounds (2e,f,h,i,m) strongly bound to the delta receptor with IC50 values in the nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were in the micromolar or greater range indicating excellent delta opioid receptor subtype selectivities. In this series, two important structure-activity relationships were found for the delta receptor binding affinity. First, the spatial orientation of the alpha-benzylic position influenced the affinities with the alpha R derivatives 2a-n generally showing more than 10-fold greater affinity than the alpha S derivatives 3a-n. Second, the binding affinities were strongly influenced by the number of alkyl substituents on the amide nitrogen. N-Monoalkylbenzamide derivatives 2b-d showed lower affinity than N,N-dialkylbenzamide derivatives 2e-n, and the N-unsubstituted benzamide derivative 2a had the lowest affinity for the delta receptor in the series. The dramatic effect of the amide group substitution pattern on the binding affinity for the delta receptor strongly suggests that the amide function is an important structural element in the interaction of this series of compounds at the delta receptor. Selective compounds in this series were examined for binding affinity in cloned human mu and delta receptors. The results obtained generally paralleled those from the rat brain binding assay. Compounds 2e,f with potent delta binding affinities and high delta selectivities were shown to be delta agonists with high selectivity by studies in the guinea pig ileum (GPI) and mouse vas deferens (MVD) preparations. Compound 2f was the most selective compound in the rat brain and GPI/MVD assays with 1755- and 958-fold delta vs mu selectivity, respectively.

Alkylation↗
PubMed1987

Improved radioreceptor assay of opiate narcotics in human serum: application to fentanyl and morphine metabolism.

A recently developed radioreceptor assay (RRA) (1) that employs 3H-naloxone and rat brain membrane homogenates was improved two ways. First, the brain membranes were preincubated in the presence of sodium ions, and second, manganase-II ions were added to the sample incubations. These changes enhanced the assay sensitivity and reproducibility with stored membrane preparations and reduced the effects of serum constituents (Na+) on ligand-receptor binding. Patient sera were assayed by radioimmunoassay (RIA) and RRA after fentanyl administration and by high-performance liquid chromatography (HPLC) and RRA after morphine administration. The results with both fentanyl assays were comparable, and no fentanyl metabolites were detectable by RRA after HPLC of serum extracts. In contrast, preliminary results with the HPLC-RRA procedure suggest the presence of an active morphine metabolite of unknown structure in sera obtained from patients on morphine therapy.

Animals↗