title: LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone.
abstract: The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)=0.81 nM) receptor than the clinically effective antidepressant, nefazodone. It is a potent inhibitor of [3H]5-HT uptake into rat cortical synaptosomes (IC(50)=3.1 nM) and shows selectivity over that for [3H]noradrenaline (IC(50)>1000 nM). It potentiates potassium-induced [3H]5-HT outflow from prelabelled guinea pig cortical slices both in the presence (EC(50)=950 nM) and absence (EC(50)=250 nM) of a saturating concentration of the 5-HT transport inhibitor, paroxetine, indicating a low level of activity at the 5-HT(1B/1D) autoreceptor. These studies indicate that LY367265 is a putative antidepressant which, because of its 5-HT(2A) receptor antagonist activity, has the potential to produce less sleep disturbance and sexual dysfunction than selective serotonin uptake inhibitors.
authors.affiliation: Eli Lilly and Company, Lilly Research Centre Ltd., Erl Wood Manor, Surrey GU20 6PH, Windlesham, UK. pullar@lilly.com
authors.forename: I A
authors.initials: IA
authors.lastname: Pullar
authors.forename: S L
authors.initials: SL
authors.lastname: Carney
authors.forename: E M
authors.initials: EM
authors.lastname: Colvin
authors.forename: V L
authors.initials: VL
authors.lastname: Lucaites
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: S
authors.initials: S
authors.lastname: Wedley
mesh_terms: D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000494:pharmacology*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology*; D014230:Triazoles / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D002352:Carrier Proteins; D003499:Cyclic S-Oxides; C417213:LY 367265; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D044402:Receptor, Serotonin, 5-HT2A; D011985:Receptors, Serotonin; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; C493232:Slc6a4 protein, rat; D013830:Thiadiazoles; D014230:Triazoles; D012701:Serotonin; C051752:nefazodone; D009638:Norepinephrine