HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole), a dopamine D4 receptor antagonist and serotonin reuptake inhibitor: characterisation of its in vitro profile and pre-clinical antipsychotic potential.

Abstract
The present study describes the pharmacological profile of the putative antipsychotic drug Lu 35-138 ((+)-(S)-3-{1-[2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl]-3,6-dihydro-2H-pyridin-4-yl}-6-chloro-1H-indole). The in vitro receptor profile of Lu 35-138 revealed high affinity (K(i)=5 nM) and competitive antagonism (K(b)=8 nM) at dopamine D(4) receptors combined with potent 5-HT uptake inhibition (IC(50)=3.2 nM) and moderate alpha(1)-adrenoceptor affinity (K(i)=45 nM). In vivo, Lu 35-138 selectively counteracted hyperlocomotion induced by d-amphetamine (0.5 mg/kg; ED(50)=4.0 mg/kg, s.c.) in rats and phencyclidine (PCP; 2.5 mg/kg; ED(50)=13 mg/kg, s.c.) in mice. Lu 35-138 was unable to affect hyperlocomotion induced by a high dose of d-amphetamine (2.0 mg/kg), which indicates a preferential action on limbic versus striatal structures. A similar limbic selectivity of Lu 35-138 was indicated in voltammetric measure of dopamine output in the core and shell subdivisions of the nucleus accumbens in rats. Furthermore, a relatively large dose of Lu 35-138 (18 mg/kg, s.c.) counteracted d-amphetamine-induced disruption of pre-pulse inhibition in rats and repeated administration of Lu 35-138 (0.31 or 1.25 mg/kg, p.o. once daily for 3 weeks) reduced the number of spontaneously active dopamine neurones in the ventral tegmental area, underlining its antipsychotic-like profile. Lu 35-138 failed to induce catalepsy in rats or dystonia in Cebus apella monkeys and did not deteriorate spatial memory in rats as assessed by water maze performance. Collectively, these results suggest that Lu 35-138 possesses antipsychotic activity combined with a low extrapyramidal and cognitive side effect liability.
AuthorsPeter Hertel, Michael Didriksen, Bruno Pouzet, Lise T Brennum, Karina K Søby, Anna Kirstine Larsen, Claus T Christoffersen, Teresa Ramirez, Monica M Marcus, Torgny H Svensson, Vincenzo Di Matteo, Ennio Esposito, Benny Bang-Andersen, Jørn Arnt
JournalEuropean journal of pharmacology (Eur J Pharmacol) Vol. 573 Issue 1-3 Pg. 148-60 (Nov 14 2007) ISSN: 0014-2999 [Print] Netherlands
PMID17689529 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • 3-(1-(2-(1-acetyl-2,3-dihydro-1H-indol-3-yl)ethyl)-3,6-dihydro-2H-pyridin-4-yl)-6-chloro-1H-indole
  • 5-(4-(4-chlorophenyl)piperazin-1-ylmethyl)-1H-indole
  • Adrenergic alpha-1 Receptor Antagonists
  • Dihydropyridines
  • Indoles
  • Piperazines
  • Serotonin Uptake Inhibitors
  • Sulfonamides
  • Citalopram
  • Benzodiazepines
  • Receptors, Dopamine D4
  • Clozapine
  • Haloperidol
  • Risperidone
  • Olanzapine
  • sonepiprazole
Topics
  • Adrenergic alpha-1 Receptor Antagonists
  • Animals
  • Animals, Outbred Strains
  • Benzodiazepines (pharmacology)
  • Cebus
  • Citalopram (pharmacology)
  • Clozapine (pharmacology)
  • Cognition (drug effects)
  • Dihydropyridines (chemistry, pharmacology)
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical (methods)
  • Female
  • Haloperidol (pharmacology)
  • Haplorhini
  • Humans
  • Indoles (chemistry, pharmacology)
  • Male
  • Mice
  • Molecular Structure
  • Motor Activity (drug effects)
  • Olanzapine
  • Piperazines (chemistry, pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Dopamine D4 (antagonists & inhibitors)
  • Risperidone (pharmacology)
  • Selective Serotonin Reuptake Inhibitors (chemistry, pharmacology)
  • Sulfonamides (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: