bemesetron and zatosetron

Specific binding of [3H]strychnine was studied on membranes prepared from rat spinal cord. Several antagonists and agonists of 5-HT3 receptors and tropane derivatives displaced [3H]strychnine binding with micromolar potencies. In the presence of 10 microM glycine a high affinity (nanomolar) component of displacement was also observed for the tropeines zatosetron, bemesetron and tropisetron. The displacing potency of glycine was also enhanced by these agents which are therefore termed glycine-positive. In contrast, atropine, SR 57227A, m-chlorophenylbiguanide, metoclopramide and granisetron are termed glycine-negative, because they decreased the displacing potency of glycine while glycine decreased the displacing potencies of atropine and metoclopramide. The dissociation of [3H]strychnine binding was accelerated in the presence of m-chlorophenylbiguanide, SR 57227A, atropine and zatosetron with a concentration dependence (EC50 values and Hill slopes) similar to their displacing effects. This demonstrates that the displacement of strychnine binding is associated with allosteric interactions between different binding sites. Structure-activity analysis revealed that the tropeine structure is essential for high affinity binding, and its substitutions (in scopolamine and cocaine) or its replacement (in ondansetron and metoclopramide) strongly decrease the potency and/or efficacy of allosteric modulation. High affinity modulatory sites for tropeines appear to be associated with the potentiation of ionophore function, but distinct from the low affinity channel blocking sites as well as from the binding sites of strychnine and glycine.

Topics: Allosteric Regulation; Animals; Benzofurans; Binding, Competitive; Bridged Bicyclo Compounds, Heterocyclic; Glycine; Granisetron; Indoles; Ligands; Male; Medulla Oblongata; Ondansetron; Pons; Rats; Rats, Wistar; Receptors, Glycine; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Serotonin Antagonists; Serotonin Receptor Agonists; Spinal Cord; Strychnine; Tropanes; Tropisetron; Tubocurarine

The 5-HT3-receptor antagonist, ondansetron, has been shown to have positive effects in selected in-vivo models of memory impairment and anxiety. The exact mechanisms underlying such bioactivities are unknown. In the present work, an 86Rb efflux bioassay was used to show that ondansetron has a unique ability to block voltage-gated potassium channels in TE671 human neuroblastoma cells. This intrinsic potassium-channel-blocking (KCB) property is relatively weak (IC50 20 microM), but is not shared by other 5-HT3-receptor ligands including zatosetron, MDL 72222, LY 278, 584, zacopride, 1-phenylbiguanide, and ICS 205-930 (tropisetron). Pre-incubation of the target neuroblastoma cells with several 5-HT-receptor ligands including 5-hydroxytryptamine, 8-OH-DPAT, ketanserin, 2-methyl-5-HT, as well as a number of potent 5-HT3 agonists and antagonists and two selective neurotoxins, failed to abolish the KCB action of ondansetron. A preliminary structure-activity relationship analysis indicates that the KCB activity of ondansetron is almost entirely attributable to its structural nucleus, 2,3-dihyro-9-methyl-4(1H)-carbazolone. It is hypothesized that the KCB action of ondansetron is mediated through receptors other than 5-HT3 receptors. The KCB activity of ondansetron may be a significant factor in the in-vivo cognition-enhancing activities of this compound, conceivably due to depolarization of the hippocampal synaptic membranes and a consequent augmentation of neurotransmission.

Topics: Anti-Anxiety Agents; Benzamides; Benzofurans; Biguanides; Bridged Bicyclo Compounds, Heterocyclic; Humans; Hypoglycemic Agents; Indazoles; Indoles; Neuroblastoma; Neurotoxins; Ondansetron; Potassium Channels; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Rubidium Radioisotopes; Serotonin Antagonists; Serotonin Receptor Agonists; Structure-Activity Relationship; Tropanes; Tropisetron; Tumor Cells, Cultured

Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

Topics: Animals; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Guinea Pigs; Heart Rate; In Vitro Techniques; Indoles; Male; Muscle Contraction; Muscle, Smooth; Rats; Rats, Inbred Strains; Serotonin Antagonists; Structure-Activity Relationship; Tropisetron