himbacine and telenzepine

Albeit time-consuming, the most rigorous method of classification of receptor subtypes is the determination of pA2 values. However, this methodology requires the knowledge of absolute concentrations of both agonists and antagonists--something that may not necessarily be calculable under certain experimental conditions. Wolfgang Kromer offers a different method for classification using antagonists which is not dependent on absolute affinities, and which has the additional advantage of speed.

Topics: Alkaloids; Binding, Competitive; Furans; Muscarinic Antagonists; Naphthalenes; Piperidines; Pirenzepine; Receptors, Muscarinic

The green mamba (Dendroaspis angusticeps) "muscarinic toxin', MT1, was radioiodinated by the chloramine T method. 125I-MT1 labelled the muscarinic M1 receptor subtype with a very good selectivity in rat brain. It had no preference for the receptor states with high or low affinity for agonists, and was not affected by Gpp(NH)p addition to the incubation medium. The 125I-MT1 binding was reversible, with a half life of 45 min at 25 degrees C. The effect of competitive and allosteric muscarinic antagonists on 125I-MT1 binding and dissociation can be rationalized by assuming that the radioiodinated toxin is able to label the muscarinic (acetylcholine) binding site.

Topics: Alkaloids; Animals; Atropine; Binding, Competitive; Brain; Carbachol; Elapid Venoms; Furans; Gallamine Triethiodide; In Vitro Techniques; Iodine Radioisotopes; Isotope Labeling; Kinetics; Muscarinic Agonists; Muscarinic Antagonists; Naphthalenes; Oxotremorine; Parasympatholytics; Pilocarpine; Piperidines; Pirenzepine; Protein Binding; Rats; Receptor, Muscarinic M1; Receptors, Muscarinic; Synaptic Membranes; Tubocurarine

1. The muscarine receptor mediating electrically-stimulated acid secretion in the mouse isolated stomach was characterized using a variety of muscarine receptor antagonists confirming the M1 nature of the antagonist effect of telenzepine. 2. Field stimulation (7 V, 10 Hz, 0.5 ms) resulted in a plateau acid secretion over at least 90 min which was completely blocked by either 1 mumol/l TTX or H2 receptor antagonists (100 mumol/l cimetidine or 10 mumol/l lupitidine). Ranitidine, which is known to potently inhibit mucosal acetylcholine esterase, was ineffective. Compound 48/80 at 100 mumol/l, which depletes mucosal histamine stores, initially mimicked electrical stimulation but subsequently prevented it from inducing acid secretion. 3. 10 muscarine receptor antagonists with differing relative affinities for M1, M2 and M3 receptors were introduced at 1 mumol/l to inhibit electrically-stimulated acid secretion. The percentages inhibition were plotted against binding affinities of the antagonists at either M1, M2 or M3 binding sites. A statistically significant correlation between functional and binding data was detected only when based on M1 affinities. 4. It is concluded that field stimulation, which probably mimicks vagal drive, results in muscarinic M1 receptor activation on paracrine cells to release histamine. Histamine then stimulates parietal cells to secrete acid. Hence, according to the present and our previous data, telenzepine inhibits acid secretion under these conditions by blocking M1 receptors at least partially located on histamine-releasing paracrine cells.

Topics: Acetylcholine; Alkaloids; Animals; Anti-Ulcer Agents; Electric Stimulation; Furans; Gastric Acid; Gastric Mucosa; Histamine; Mice; Muscarinic Antagonists; Naphthalenes; p-Methoxy-N-methylphenethylamine; Parasympatholytics; Piperidines; Pirenzepine; Stomach; Thiazepines; Vagus Nerve