5-HT1A receptor antagonists(Serotonin 1a (5-HT1a) receptor antagonists), 5-HT2A receptor antagonists(Serotonin 2a (5-HT2a) receptor antagonists), D1 receptor agonists(Dopamine D1 receptor agonists)

+ [1]

Therapeutic Areas

Nervous System DiseasesEndocrinology and Metabolic Disease

Active Indication-

Inactive Indication

Parkinson Disease

Originator Organization

Lek Pharmaceuticals dd

Active Organization-

Inactive Organization

Lek Pharmaceuticals dd

Drug Highest PhasePendingDiscovery

First Approval Date-

Regulation-

100 Clinical Results associated with LEK-8829

100 Translational Medicine associated with LEK-8829

100 Patents (Medical) associated with LEK-8829

Literatures (Medical) associated with LEK-8829

01 Jun 2004·Naunyn-Schmiedeberg's Archives of PharmacologyQ4 · MEDICINE

The dopamine D1 receptor agonist and D2 receptor antagonist LEK-8829 attenuates reinstatement of cocaine-seeking in rats

Q4 · MEDICINE

Article

Author: Milivojevic, Natasa ; Zivin, Marko ; Sket, Dusan ; Krisch, Igor

Various dopaminergic drugs have been studied for their efficacy in the treatment of cocaine addiction. Pretreatment with either selective dopamine D1 receptor agonists or selective dopamine D2 receptor antagonists prevents reinstatement of cocaine-seeking in animal models of drug craving and relapse. We tested a novel ergoline derivative with combined D1 agonistic and D2 antagonistic effects, 9,10-didehydro- N-methyl- N-(2-propynyl)-6-methyl-8beta-aminomethylergoline bimaleate (LEK-8829), for its effects on cocaine-seeking in the intravenous cocaine self-administration model in rats. Pretreatment with systemic injections of LEK-8829 attenuated reinstatement of cocaine-seeking induced by cocaine priming injections and diminished cocaine intake in cocaine self-administration sessions. LEK-8829 itself did not induce reinstatement of cocaine-seeking and did not maintain intravenous self-administration. The results of our study indicate that LEK-8829 is a candidate medication for the treatment of cocaine craving in cocaine addiction.

01 Feb 2002·Molecular PharmacologyQ3 · MEDICINE

Modulation of Neuroleptic Activity of 9,10-Didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline Bimaleinate (LEK-8829) by D1 Intrinsic Activity in Hemi-Parkinsonian Rats

Q3 · MEDICINE

Article

Author: Dus̆an Sket ; Gordana Glavan ; Marko Z̆ivin

Parkinsonism, a common unwanted side effect of typical antipsychotic (neuroleptic) drugs, is induced by the blockade of striatal dopamine D2 receptors. In rats with hemi-parkinsonism induced by unilateral lesion of dopaminergic nigrostriatal neurons with 6-hydroxydopamine, D2 antagonists inhibit contralateral turning induced by D2 agonists and augment the levels of neurotensin mRNA in dopaminergically intact striatum. By contrast, D1 agonists induce contralateral turning and augment neurotensin mRNA levels in dopamine-depleted striatum. These effects could be inhibited by D1 but not by D2 antagonists. Here we used a hemi-parkinsonian model to investigate the effects of putative D1 agonist/D2 antagonist LEK-8829 (9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8-aminomethylergoline bimaleinate), an experimental antipsychotic, on turning behavior and the expression of striatal neurotensin, preprotachykinin and neurotransmitter-induced early gene protein 4 (ania-4) mRNAs. We found that LEK-8829 inhibited contralateral turning induced by D2 agonist quinpirole, but only if the rats were cotreated with D1 antagonist SCH-23390. In situ hybridization showed that LEK-8829 induced the expression of neurotensin and ania-4 mRNAs in dopamine-intact striatum that could be completely blocked only by the combined treatment with SCH-23390 and quinpirole. In addition, LEK-8829 augmented the expression of neurotensin, preprotachykinin and ania-4 mRNAs in dopamine-depleted striatum that could be completely blocked by SCH-23390. This study clearly demonstrates that in hemi-parkinsonian rats D1 agonistic activity of LEK-8829 confers its anti-parkinsonian drug-like properties and modulates its neuroleptic drug-like properties, which are dependent on the blockade of dopamine D2 receptors. These findings imply that atypical antipsychotics with D1 intrinsic activity might have a reduced propensity for the induction of extrapyramidal syndrome.

01 Mar 1999·The Journal of pharmacology and experimental therapeutics

Ergoline derivative LEK-8829-induced turning behavior in rats with unilateral striatal ibotenic acid lesions: interaction with bromocriptine.

Article

Author: Sprah, L ; Sket, D ; Zivin, M

LEK-8829 [9,10-didehydro-N-methyl-(2-propynyl)-6-methyl-8- aminomethylergoline bimaleinate] is an antagonist of dopamine D2 receptors and serotonin (5-HT)2 and 5-HT1A receptors in intact animals and a D1 receptor agonist in dopamine-depleted animals. In the present study, we used rats with unilateral striatal lesions with ibotenic acid (IA) to investigate the dopamine receptor activities of LEK-8829 in a model with innervated dopamine receptors. The IA-lesioned rats circled ipsilaterally when challenged with apomorphine, the mixed agonist on D1/D2 receptors. LEK-8829 induced a dose-dependent contralateral turning that was blocked by D1 receptor antagonist SCH-23390. The treatment with D1 receptor agonist SKF-82958 induced ipsilateral turning, whereas the treatment with D2 receptor antagonist haloperidol induced contralateral posture. The combined treatment with SKF-82958 and haloperidol resulted in a weak contralateral turning, indicating the possible receptor mechanism of contralateral turning induced by LEK-8829. Bromocriptine induced a weak ipsilateral turning that was blocked by haloperidol. The ipsilateral turning induced by bromocriptine was significantly potentiated by the coadministration of a low dose but not by a high dose of LEK-8829. The potentiation of turning was blocked either by SCH-23390 or by haloperidol. The potentiation of ipsilateral turning suggests the costimulation of D2 and D1 receptors by bromocriptine and LEK-8829, respectively, whereas the lack of potentiation by the highest dose of LEK-8829 may be explained by the opposing activity of LEK-8829 and bromocriptine at D2 receptors. We propose that the D2 and 5HT2 receptor-blocking and D1 receptor-stimulating profile of LEK-8829 is promising for the treatment of negative symptoms of schizophrenia.

100 Deals associated with LEK-8829

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Discovery	SI	Lek Pharmaceuticals dd	-

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