title: The anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor subtypes in rat brain: sensitivity to guanine nucleotides.
abstract: Eltoprazine (DU 28853) inhibits offensive aggressive behaviour in several animal species. We characterized the binding of radiolabelled eltoprazine in rat brain by autoradiography. [3H]Eltoprazine displayed saturable and high-affinity binding to several brain areas, including the basal ganglia, hippocampal formation and cerebral cortex (Kd values ranging from 4.2 to 9.5 nM). The maximal binding capacities (Bmax) for [3H]eltoprazine were similar to those for [3H]5-HT and were highest in the substantia nigra and subiculum. Competition with eltoprazine for [3H]ligand binding to the various 5-HT1 receptor subtypes revealed preferential binding to 5-HT1A (IC50 values ranging from 42 to 50 nM) and 5-HT1B (IC50 values ranging from 25 to 38 nM) recognition sites. The drug had moderate affinity for 5-HT1C sites (IC50 = 282 nM). Addition of GTP or its stable analogue Gpp(NH)p to the radioligand assay caused a marked reduction (50-90%) in both [3H]eltoprazine and [3H]5-HT binding. These effects were substantially less in the choroid plexus. The binding of the antagonist (-)[125I]Iodocyanopindolol ([125I]ICYP) to 5-HT1B recognition sites, as quantified in the subiculum and substantia nigra, was either unaltered or slightly enhanced by the addition of 10(-3) M GTP. Furthermore, GTP did not affect the competition for [125I]ICYP binding by the 5-HT1-antagonist methiothepin, whereas it did significantly reduce the displacement by eltoprazine, resulting in an almost twofold increase in IC50 values. The data indicate that the anti-aggressive drug eltoprazine preferentially binds to 5-HT1A and 5-HT1B receptor sites and that this interaction is modulated by guanine nucleotides.
authors: Department of Pharmacology, Duphar B.V., Weesp, The Netherlands.
authors: H
authors: H
authors: Sijbesma
authors: J
authors: J
authors: Schipper
authors: E R
authors: ER
authors: De Kloet
mesh_terms: D000374:Aggression / Q000187:drug effects*; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D020120:Iodocyanopindolol; D007700:Kinetics; D010869:Pindolol / Q000031:analogs & derivatives; D010879:Piperazines / Q000378:metabolism* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000494:pharmacology
chemical_list: D006150:Guanine Nucleotides; D007457:Iodine Radioisotopes; D010879:Piperazines; D011985:Receptors, Serotonin; C018406:1-(3-trifluoromethylphenyl)piperazine; D012701:Serotonin; D006165:Guanylyl Imidodiphosphate; C063828:eltoprazine; D020120:Iodocyanopindolol; D006160:Guanosine Triphosphate; D010869:Pindolol