Regulation of L-Type Calcium Channels in GH4 Cells via A1 Adenosine Receptors

Abstract: Identification of A₁ adenosine receptors (A₁Rs) in a tumor cell line derived from rat pituitary (GH₄ cells) was performed by ligand binding and immunological experiments. Subsequently, the involvement of A₁Rs in the regulation of calcium conductance was studied in these cells. The agonist N ⁶-( R )-(2-phenylisopropyl)adenosine ( R -PIA) did not modify the intracellular calcium basal levels, whereas it inhibited the increase produced by 15 m M KCl depolarization. The antagonist 1,3-dipropyl-8-cyclopentylxanthine led to the opening of voltage-dependent cell surface calcium channels in the absence of exogenous KCl. The channels were of the L type because the effect was abolished by calciseptine and by verapamil. These results suggest that endogenous adenosine exerts a tonic inhibitory effect on calcium transport. This was confirmed by the high adenosine concentration found in cell supernatants (up to 1 µ M ) and by the calcium mobilization produced by exogenously added adenosine deaminase. In depolarizing conditions, the calcium peak in the presence of adenosine deaminase was reduced when cells were preincubated with R -PIA, thus suggesting that A₁R activation regulates the intensity of depolarization. These results demonstrate that adenosine is an important regulator of the physiological state of pituitary tumor cells by modulating, in an autocrine manner, the activity of L-type voltage-dependent calcium channels.     

Bacterial Antagonists of Aspergillus flavus

In order to search for bacteria capable of reducing the aflatoxin contamination of cottonseed, 892 indigenous bacterial isolates, including 11 that were endophytic to cotton, were screened for their ability to inhibit the growth of Aspergillus flavus on cottonseed in an in vitro bioassay. Only six isolates partially or totally inhibited fungal growth. All antagonistic isolates were recovered from boll, lint or seed surface or from the lint of mature bolls. One was retrieved from mature seeds. None of the endophytic isolates showed activity. In four field trials, the incidence of A. flavus -induced damage to locules inoculated simulteously with A. flavus plus the most A. flavus plus the most effective antagonistic isolate (D1) was reduced by 41-100% relative to locules inoculated with A. flavus alone. The severity of damage to locules inoculated simultaneously with A. flavus and with D1 was reduced by 60-l00% relative to locules inoculated with A. flavus alone. Isolate D1, identified as Pseudomonas cepacia, completely inhibited the growth of A. flavus on synthetic media.     

Endogenous opiates: 1980

Vast amounts of research have been done that have attempted to delineate the pharmacological and physiological effects of the endogenous opiate peptides. A great deal of knowledge has also been accumulated in a limited time span concerning the types and locations of the opiate receptors and peptides, as well as their functions. In 1980, reports were made concerning the effects of these peptides on analgesia, on tolerance and dependence, on activity, on learning and memory, on schizophrenia and other types of emotional disturbances, and on physiological responses such as eating and drinking, cardiovascular responses, and sexual function. Additional understanding was also gained concerning their interactions with neurotransmitters, other neuropeptides, and hormones. These and other studies published only in 1980 are reviewed in this paper, which is the third of an annual series.     

Effect of ring-constrained phenylpropyloxyethylamines on sigma receptors

A series of ring-constrained phenylpropyloxyethylamines, partial opioid structure analogs and derivatives of a previously studied sigma (σ) receptor ligand, was synthesized and evaluated at σ and opioid receptors for receptor selectivity. The results of this study identified several compounds with nanomolar affinity at both σ receptor subtypes. Compounds 6 and 9 had the highest selectivity for both σ receptor subtypes, compared to μ opioid receptors. In addition, compounds 6 and 9 significantly reduced the convulsive effects of cocaine in mice, which would be consistent with antagonism of σ receptors.     

Tricyclic aminopyrimidine histamine H4 receptor antagonists

This report discloses the development of a series of tricyclic histamine H(4) receptor antagonists. Starting with a low nanomolar benzofuranopyrimidine HTS hit devoid of pharmaceutically acceptable properties, we navigated issues with metabolism and solubility to furnish a potent, stable and water soluble tricyclic histamine H(4) receptor antagonist with desirable physiochemical parameters which demonstrated efficacy a mouse ova model.     

Antagonism of the ATP-gated P2X7 receptor: a potential therapeutic strategy for cancer

Purinergic Signalling - The P2X receptor 7 (P2X7R) is a plasma membrane receptor sensing extracellular ATP associated with a wide variety of cellular functions. It is most commonly expressed on...     

A comparative binding study of modified bovine immunodeficiency virus TAR RNA against its TAT peptide

Besides generating novel binding peptides or small molecules to their RNA target, successful design of chemically modified RNA constructs capable of tighter binding with their binding peptides is also of significant importance. Herein, the synthesis and binding studies of a series of both wt and mutant bovine immunodeficiency virus (BIV) TAR RNA constructs against its Tat peptide are reported. Understanding the requirements that enable RNA construct binding properties, especially at the hairpin loop or internal bulge, would afford potential therapeutic approaches to control the BIV life cycle.     

In vitro modulatory effects of functionalized pyrimidines and piperidine derivatives on Aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) activities

The development of biologically active molecules based on molecular recognition is an attractive and challenging task in medicinal chemistry and the molecules that can activate/deactivate certain receptors are of great medical interest. In this contribution, selected pyrimidine/piperidine derivatives were synthesized and tested for the ability to activate/deactivate Aryl hydrocarbon receptor (AhR) and Glucocorticoid receptor (GR). Tested compounds are shown to activate the receptors but to much lesser extent than positive controls, dioxin and dexamethasone for Ahr and GR, respectively. However, some of them antagonized the positive controls action. Although further in vivo studies are needed to fully characterize the bioactivities of these compounds, the reported in vitro evidences demonstrate that they might be used as the modulators of AhR and GR activities.     

Discovery of potent, selective, orally active benzoxazepine-based Orexin-2 receptor antagonists

During our efforts to identify a series of potent, selective, orally active human Orexin-2 Receptor (OX2R) antagonists, we elucidated structure-activity relationship (SAR) on the 7-position of a benzoxazepine scaffold by utilizing Hammett σ(p) and Hansch-Fujita π value as aromatic substituent constants. The attempts led to the discovery of compound 1m, possessing good in vitro potency with over 100-fold selectivity against OX1R, good metabolic stability in human and rat liver microsome, good oral bioavailability in rats, and in vivo antagonistic activity in rats by oral administration.