Louis A. Cohen

Palladium-catalysed synthesis of heterocondensed pyrroles

Abstract The palladium-catalysed preparation of some heterocondensed pyrroles from ortho nitrogen containing hetaryl iodides and derivatives of propargyl alcohol is described.

Fluoroimidazoles as antiviral agents and inhibitors of polynucleotide biosynthesis

Abstract 4-fluoroimidazole (4-FI), 4-fluoroimidazole-5-carboxylic acid (4-FIC), 4-fluoroimidazole-5-carboxamide (4-FICA), and 5-fluoro-1-β-D-ribofuranosylimidazole-4-carboxamide (5-FICAR), have been studied for their inhibitory effects on viral cytopathogenecity in a variety of assay systems encompassing nearly all major virus groups. Ribavirin (1-β-D-ribofuranosyl-1,2,4-triazole-3-carbox-amide), 5-AICAR (5-amino-1-β-D-ribofuranosylimidazole-4-carbox-amide), and poly(I)βpoly (C) were included as reference materials. Although the antiviral activities of ribavirin and the fluoroimidazoles varied considerably from one system to another, the relative order of activity remained constant: ribavirin >5-FICAR > 5-AICAR > 4-FICA. 4-FIC and 4-FI were inactive. Poly(I)βpoly (C) exhibited a spectrum of antiviral activity that differed totally from that of 5-FICAR and the other compounds. Unlike 5-AICAR, both 5-FICAR and ribavirin inhibited cellular DNA3 and RNA synthesis, as determined by [3H-methyl]thymidine and [3H-5]uridine incorporation, respectively, at concentrations which coincided quite well with those inhibiting viral cytopathogenicity. Hence, 5-FICAr and ribavirin may owe their broad-spectrum antiviral activity to inhibition of nucleic acid synthesis in the infected cell.

A novel approach to bz-substituted tryptophans via Pd-catalysed coupling / annulation.

Abstract The Pd-catalysed preparation of bz-substituted tryptophans and their derivatives, starting from 2-iodoanilines and γ,δ-acetylenic amino acid derivatives, is reported.

Synthesis of ring-halogenated histidines and histamines☆

Abstract Series of ring-halogenated histidines and histamines have been synthesized from the suitably protected parent bioimidazoles. The 5-X and 2,5-X2-derivatives are obtained by direct electrophilic halogenation while 2-X derivatives (X= Br and I) are prepared by regiospecific electrophilic dehalogenation at C-5.

SYNTHESIS OF NOVEL RING-SUBSTITUTED HISTIDINES AND HISTAMINES

Synthesis of novel 2-cycloalkyl-L-histidines and 2-cycloalkylhistamines via radical alkylation with cycloalkylcarboxylic acids and silver nitrate in the presence of 10% H2SO4 by ammonium persulfate is described. The method is also extended to the synthesis of 1,2-dialkyl-L-histidines and 1,2-dialkylhistamines.

Differential effect of fluorinated analogs of TRH on the cardiovascular system and prolactin release

The effects of thyrotropin-releasing hormone (TRH) and the TRH-analogs, 4-fluoro-Im-TRH (4-F-TRH) and 2-trifluoromethyl-Im-TRH (2-TFM-TRH), on the cardiovascular system and prolactin (PRL) release were examined in conscious rats. TRH (2.8 or 28 nmol) injected into the anterior hypothalamus produced dose-dependent increments in blood pressure and heart rate; plasma PRL was increased twofold after the higher dose of TRH. 4-F-TRH had effects similar to those of TRH on both the cardiovascular and PRL response. In contrast, the 2-TFM-TRH was significantly less active than TRH or 4-F-TRH in eliciting tachycardia, yet was noticeably more potent in affecting PRL release. These data suggest that the receptors for TRH-induced PRL release may be different from TRH-receptors which mediate central cardiovascular responses.

First direct fluorination of tyrosine-containing biologically active peptides

Abstract Using acetyl hypoflurite a regiospecific electrophilic fluorination of the tyrosine ring of the N-terminal tetrapeptide amide (Tyr-D-Ala-Phe-Gly-NH 2 ) sequence of the opiate peptide dermorphin has been achieved in good yields.

Receptor binding of fluorinated histidine analogs of thyrotropin-releasing hormone in various regions of the rat brain

Binding properties of [4(5)-fluoro-imidazole-His2]-TRH (4(5)-F-TRH), [2-trifluoromethyl-imidazole-His2]-TRH (2-CF3-TRH) and [4(5)-trifluoromethyl-imidazole-His2]-TRH (4(5)-CF3-TRH), three novel TRH analogs, have been evaluated in rat pituitary, hypothalamus, brainstem and cortex tissue. 4(5)-F-TRH, previously shown to elicit arterial pressor responses and prolactin release similar to those of TRH, binds to TRH receptors with low, micromolar affinity (Ki = 7.5-13.5 microM). 2-CF3-TRH, an analog of less cardiovascular but increased prolactin-releasing activity, shows Ki values of 3.3-4.9 microM. 4(5)-CF3-TRH, which shows comparable biological activity to 2-CF3-TRH, demonstrates a binding affinity which is virtually nonspecific (Ki = 0.39-1.01 mM). It is therefore concluded that the biological effects of these analogs are mediated either through low affinity TRH binding sites not recognized by [3H][3Me-His2]-TRH or through mechanisms not involving TRH receptors as such.

A SURVEY OF NONXANTHINE DERIVATIVES AS ADENOSINE RECEPTOR LIGANDS

The binding affinities at rat A1, A2a, and A3 adenosine receptors of a wide range of heterocyclic derivatives have been determined. Mono-, bi-, tricyclic and macrocyclic compounds were screened in binding assays, using either [3H]PIA or [3H]CGS 21680 in rat brain membranes or [125I]AB-MECA in CHO cells stably transfected with rat A3 receptors. Several new classes of adenosine antagonists (e.g. 5-oxoimidazopyrimidines and a pyrazoloquinazoline) were identified. Various sulfonylpiperazines, 11-hydroxytetrahydrocarbazolenine, 4H-pyrido[1,2-a]pyrimidinone, folic acid, and cytochalasin H and J bound to A3 receptors selectively. Moreover, cytochalasin A, which bound to A1 adenosine receptors with Ki value of 1.9 μM, inhibited adenylyl cyclase in rat adipocytes, but not via reversible A1 receptor binding.

Norvaline2-TRH : binding to TRH receptors in rat brain homogenates

Norvaline2-thyrotropin-releasing hormone ([Nva2]TRH) has been described as a thyrotropin-releasing hormone (TRH) analog with no thyrotropin (TSH)-releasing capacity but enhanced analeptic activity compared with TRH, as shown by the reversal of haloperidol-induced catalepsy. We have evaluated the receptor-binding properties of [Nva2]TRH in homogenates of rat anterior pituitary, hypothalamus, brainstem and cortex tissue, using [3H]TRH and [3H][3-Me-His2]TRH as radioligands. Apparent Ki values at high affinity TRH-binding sites, labelled predominantly by [3H][3-Me-His2]TRH, ranged from 17.0 to 36.9 microM in all tested regions. Additionally, [Nva2]TRH was shown to compete with [3H]TRH at low affinity TRH-binding sites with similar affinities. It is concluded that the loss of TSH-releasing activity of [Nva2]TRH appears to be due to a drastic reduction in binding affinity to the high affinity TRH receptor subtype. Its analeptic activity, however, may be mediated by low affinity TRH binding sites which are predominantly labelled by [3H]TRH or by yet unidentified mechanisms.