BIIR 561 CL: a novel combined antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and voltage-dependent sodium channels with anticonvulsive and neuroprotective properties.

Antagonists of glutamate receptors of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype, as well as of voltage-gated sodium channels, exhibit anticonvulsive and neuroprotective properties in vivo. One can postulate that a compound that combines both principles might be useful for the treatment of disorders of the central nervous system, like focal or global ischemia. Here, we present data on the effects of dimethyl-(2-[2-(3-phenyl-[1,2, 4]oxadiazol-5-yl)-phenoxy]ethyl)-amine hydrochloride (BIIR 561 CL) on neuronal AMPA receptors and voltage-dependent sodium channels.

Antagonistic properties of McNeil-A-343 at 5-HT4 and 5-HT3 receptors.

1. This study describes the in vitro interaction of the muscarinic ligand McNeil-A-343 with two 5-hydroxytryptamine (5-HT) receptor subtypes, the 5-HT4 and 5-HT3 receptors, using functional as well as radioligand binding studies. 2.

Medicinal chemistry of muscarinic agonists for the treatment of dementia disorders.

Alzheimer disease (AD) is a neurodegenerative disorder lacking an effective therapy. The etiology is controversial and among different drug strategies, the cholinergic approach has gained great interest owing to biochemical and pharmacological evidence of the crucial role of acetylcholine in cognitive functions. Several attempts exploiting the boosting of the cholinergic system are currently under way.

Gastroprokinetic properties of the benzimidazolone derivative BIMU 1, an agonist at 5-hydroxytryptamine4 and antagonist at 5-hydroxytryptamine3 receptors.

We have investigated the in vivo motor stimulating and gastroprokinetic properties of the azabicycloalkyl benzimidazolone derivative BIMU 1 (3-ethyl-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride) and its binding profile at 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptors, in an attempt to assess the serotonergic mechanism underlying its prokinetic action.

Himbacine discriminates between putative muscarinic M1 receptor-mediated responses.

This study describes the antagonistic properties of himbacine, in comparison with those of pirenzepine, at muscarinic receptors mediating the depolarization of rat superior cervical ganglion, the inhibition of electrically-induced twitch contractions of rabbit vas deferens and the contraction of dog saphenous vein, currently classified as putative muscarinic M1 sites. The affinity of himbacine for the vas deferens site (pA2 8.08) was nearly ten times higher than those for the M1 receptors of rat ganglion and dog saphenous vein (pA2 7.

WAL 2014--a muscarinic agonist with preferential neuron-stimulating properties.

The ability of WAL 2014 to elicit muscarinic responses was investigated in various in vitro and in vivo models. In CHO cells transfected with human m1- or m3- receptor genes, WAL 2014 was clearly more effective in stimulating the M1-mediated PI response. In isolated tissue preparations, WAL 2014 exhibited full agonist properties in the rabbit vas deferens (putative M1 receptor) and behaved like a partial agonist at M2 receptors in the atrium and M3 receptors in the ileum of guinea-pigs.

DAU 6285: a novel antagonist at the putative 5-HT4 receptor.

The antagonistic properties of DAU 6285, an azabicycloalkyl benzimidazolone derivative, at putative 5-hydroxytryptamine4 (5-HT4) receptors were investigated in in vitro preparations of guinea-pig ileum and human atrium, in comparison to ICS 205-930. DAU 6285 behaved as a competitive antagonist in all the preparations examined. Its affinity (pA2) ranged between 6.

Pharmacological properties of a novel class of 5-HT3 receptor antagonists.

The pharmacological profile of six representative members of a novel class of 5-HT3 receptor antagonists is described. The compounds are esters and amides of benzimidazolone-1-carboxylic acid with a basic azabicycloalkyl moiety (compounds 1-3) and their respective ethyl derivatives (compounds 4-6). In isolated preparations (rabbit heart and guinea pig ileum) all compounds antagonized the 5-HT3 receptor-mediated effects of serotonin, with potencies comparable with those of the reference compounds, ICS 205.

Antiemetic activity of the new 5-HT3 antagonist DAU 6215 in animal models of cancer chemotherapy and radiation.

The antiemetic activity of DAU 6215, a novel antagonist of 5-HT3 receptors, was investigated in animal models of cytotoxic treatment-evoked emesis and compared with the antiemetic activity of ondansetron and metoclopramide. In dogs, vomiting was induced by i.v.

5-Hydroxytryptamine affects rat migrating myoelectric complexes through different receptor subtypes: evidence from 5-hydroxytryptophan administration.

The effect of the serotonin precursor 5-hydroxytryptophan (5-HTP) on jejunal migrating myoelectric complexes (MMCs) was investigated in conscious rats. Subcutaneous administration of low doses of 5-HTP (1-2 mg/kg) shortened the period between migrating complexes, whereas high doses of the compound (4-8 mg/kg) disrupted the MMC pattern. The serotonin (5-HT2) antagonist methysergide (8 mg/kg s.

Contraction of the colon induced by intra-aortic injection of cholinomimetic agents: a procedure for estimating spasmolytic activity in the anaesthetized rat.

An in vivo model for evaluating spasmolytic activity in the anaesthetized rat has been developed. A peculiarity of this model is the injection of parasympathetic agonists directly into the abdominal aorta. Acetylcholine and carbachol produced constant contractions of the ascending colon, while the cardiovascular system was affected only to a small extent.

Role of muscarinic receptor subtypes in the regulation of migrating myoelectric complex in the dog.

The role played by muscarinic receptor subtypes in the regulation of the migrating myoelectric complex was investigated in 7 dogs chronically implanted with bipolar electrodes along the small intestine. Pirenzepine (3-300 micrograms/kg i.v.

Cimetropium bromide: in vitro and in vivo evaluation of spasmolytic activity on human and dog colon.

The present study investigates the spasmolytic properties of cimetropium bromide, compared to atropine, on human and canine large bowel. The drug behaved as a competitive antagonist of muscarinic-mediated contractions in isolated colonic preparations from both species, with affinity values (pA2) ranging between 7.41 and 7.

Pharmacological characterization of muscarinic receptors involved in McN-A-343-induced effects on intestinal motility and heart rate in conscious dogs.

1. Intravenous injection of the muscarinic agonist, McN-A-343, in conscious dogs equipped with an ileal Thiry fistula produced a dose-related inhibition of intestinal phasic contractile activity, and an increase in heart rate. 2.

A model for studying saliva secretion in the conscious dog.

Parotid saliva secretion was studied in conscious dogs in which a chronic fistula of the parotid duct was provoked by a simple surgical procedure. To validate the technique employed, the responsiveness of the gland to various stimuli was examined. The volume of secretion was measured as well as the concentrations of Na+, K+ and calcium.

Involvement of alpha-1 and alpha-2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat.

The effects of phentolamine, yohimbine and prazosin on laparotomy induced intestinal motor disturbances were studied in anaesthetised fasted rats previously equipped with electrodes, chronically implanted on the duodenum and jejunum. During continuous recording of interdigestive myoelectric activity, laparotomy under thiopental anaesthesia (Nesdonal 40 mg/kg ip) induced a primary phase of total inhibition of spiking activity lasting 26.1 +/- 1.

N-butyl hyoscine exerts local spasmolytic effect in the small and large bowel of the conscious dog.

The spasmolytic activity of N-Butyl Hyoscine (NBH) (1) has been investigated in conscious dogs provided with ileal or colonic Thiry fistulas in which motility was stimulated by intraluminal distension. In ileal motility experiments, phasic motility index (PMI), intestinal tonus, contraction frequency and heart rate were monitored. Intravenous administration of NBH (10 to 100 micrograms/kg) depressed PMI (ED50 35.

Cimetropium: characterization of antimuscarinic and spasmolytic properties.

Cimetropium displaced 3H-NMS binding from membranes derived from gastrointestinal smooth muscle. The affinity of cimetropium for intestinal muscarinic receptors was in the range 70-100 nM. The competitive antagonism of cimetropium was demonstrated in guinea-pig ileum and taenia coli stimulated by bethanechol.

Possible mechanisms of action of caerulein on intestinal motility of sheep.

The authors report the stimulatory effects provoked by caerulein on caecum and colon motilities in sheep which are quite opposite to those exerted by the same peptide on the forestomach and abomasal sections. By means of various pharmacological tools these effects are suggested to be attributable to a direct effect of caerulein on the smooth muscle of these viscera through the involvement of receptors different from those ones on which CCK may be antagonizable by proglumide or cGMP pretreatments.