Bradley V. Clineschmidt

SARAFOTOXIN S6C : AN AGONIST WHICH DISTINGUISHES BETWEEN ENDOTHELIN RECEPTOR SUBTYPES

In contrast to endothelin-1 (ET-1) and several of its analogues, sarafotoxin S6c (S6c) was a much more potent inhibitor of [125I]-ET-1 binding in rat hippocampus and cerebellum (Ki approximately 20 pM) than in rat atria and aorta (Ki approximately 4500 nM), suggesting the existence of ET-1 receptor subtypes (aorta/atria, ETA; hippocampus/cerebellum, ETB). S6c was a potent activator of PI turnover in hippocampus (EC50 approximately 10 nM) but not atria (EC50 greater than 1 microM), unlike ET-1 which was active in both tissues. S6c, therefore, is a highly selective ETB agonist. Furthermore, S6c was a potent pressor agent in the pithed rat (ED25 mm Hg approximately 0.1 nmoles/kg, i.v.), suggesting that the ETB receptor subtype may be important in cardiovascular function.

Radioligand binding studies reveal marked species differences in the vasopressin V1 receptor of rat, rhesus and human tissues.

The [3H]arginine-vasopressin ([3H]AVP) binding site in rat, rhesus and human liver and nonpregnant human uterus was characterized and contrasted. [3H]AVP bound with high affinity (Ki values, 0.2-0.6 nM) to preparations of all tissues studied. Competition binding studies using a series of compounds from three structural classes indicate a marked species difference between the rat and primate liver AVP-V1 site. This site in rhesus and human liver however, is essentially identical, indicating that the rhesus liver is an appropriate surrogate for human tissue. These studies also indicate that the AVP-V1 site of nonpregnant human uterus and human liver is equivalent.

[3H] L-657, 743 (MK-912): a new, high affinity, selective radioligand for brain α2-adrenoceptors

Abstract L-657, 743 (MK-912), a highly potent and selective α 2 -adrenoceptor antagonist was tritiated to a high specific activity and its binding characteristics to brain tissue were determined. The specific binding of [ 3 H]L-657, 743 to rat cerebrocortex was saturable, reversible, and dependent on tissue concentration. In saturation studies, [ 3 H]L-657, 743 binding was resolved into two high affinity components exhibiting Kd values of 86 pM and 830 pM with densities of 82 fmol/mg protein and 660 fmol/mg protein, respectively. Based on the binding potencies of a variety of compounds with differing receptor selectivities, the sites labeled by [ 3 H]L-657, 743 were characteristic of α 2 -adrenoceptors. In contrast to α 2 -antagonists, α 2 -agonists displayed shallow competition curves. In the presence of 100 μM GTP, Gpp(NH) p or 150 mM NaCl, the competition curve for epinephrine was shifted to the right, whereas that for yohimbine was unaffected. In studies utilizing human cerebrocortical tissue, [ 3 H]L-657, 743 also bound with high affinity to sites characteristic of α 2 -adrenoceptors.

Effect of the benzodiazepine receptor antagonist Ro 15-1788 on the anticonvulsant and anticonflict actions of MK-801

MK-801, phenobarbital and clonazepam blocked convulsions elicited in mice by bicuculline. Treatment with Ro 15-1788 antagonized the anticonvulsant action of clonazepam, but not MK-801 or phenobarbital. The anticonflict effect in the rat of chlordiazepoxide, but not MK-801, was antagonized by Ro 15-1788. Despite having certain benzodiazepine-like effects in vivo, MK-801 does not act directly or indirectly via receptors for benzodiazepines.

Potent dopamine agonist activity of a novel ergoline, 6-Ethyl-9-oxaergoline (EOE)

6-Ethyl-9-oxaergoline (EOE) and its enantiomers were compared with apomorphine in a number of tests designed to measure dopamine (DA) agonist activity within the central nervous system. In rats, the tests were: interaction with DA receptors labeled with 3H-apomorphine or 3H-spiroperidol; the effects on DA synthesis as assessed by the gamma-butyrolactone procedure; turning in 6-OHDA lesioned animals; stereotypy; and, slowing of DA cell firing rates. In the mouse, locomotor activity, hypothermia and postural asymmetry in caudectomized animals were studied. Emesis in the beagle was also examined. The (-)-enantiomer of EOE was more potent than either the (+)-enantiomer or the racemate in all tests. With the exception of inducing stereotypy and the displacement of 3H-apomorphine from rat striatal membranes, (-)-EOE was equi- or more potent than apomorphine in all test procedures. (-)-EOE was effective following oral administration and exhibited a longer duration of action than apomorphine. The results indicate EOE is a potent DA agonist.

Famotidine: An appraisal of its mode of action and safety

Famotidine is a potent histamine (H2)-receptor antagonist that binds to the H2 receptor in a competitive reversible manner as shown by in vivo, in vitro, and clinical studies. Famotidine has shown no evidence of carcinogenicity, mutagenicity, or teratogenicity in extensive and adequately designed safety assessment studies. The drug produces neither prolonged anacidity nor doses its use result in significant elevations of serum gastrin levels beyond those seen with other available H2-receptor antagonists when used as recommended for the treatment of ulcer disease. Taken together, these data demonstrate no undue or disproportionate risk to the use of famotidine.