Delving into the Latest Updates on LY-293284 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

LY 293284

Target

5-HT1A receptor

Mechanism

5-HT1A receptor agonists(Serotonin 1a (5-HT1a) receptor agonists)

Therapeutic Areas

Nervous System Diseases

Active Indication-

Inactive Indication

Depressive Disorder, Major

Originator Organization

Eli Lilly & Co.

Active Organization-

Inactive Organization

Eli Lilly & Co.

Drug Highest PhasePendingPreclinical

First Approval Date-

Regulation-

Structure

Molecular FormulaC19H26N2O

InChIKeyCKYZLYQSDNLGPT-HNNXBMFYSA-N

CAS Registry141318-62-9

In-vitro studies have shown that WAY 100635 is not only a potent 5-HT1A antagonist, but also has high affinity and efficacy at the dopamine D(4) receptor. Nevertheless, the behavioral effects of this compound have not been investigated. This study sought to characterize the discriminative stimulus effects produced by WAY 100635. Male Sprague-Dawley rats were trained in a two-lever, fixed ratio 50, food-reinforced task with WAY 100635 (10 micromol/kg) as a discriminative stimulus. Substitution tests with different doses of WAY 100635 and (-)-pindolol, and combination tests with two 5-HT1A agonists, 8-OH-DPAT and LY 293284; and two dopamine D(4) antagonists, sonepiprazole and A-381393, were performed. Rats trained with a low dose (0.74 micromol/kg) of WAY 100635 could not learn the discrimination task after more than 3 months of sessions. Rats trained to discriminate 10 micromol/kg of WAY 100635 from saline achieved the criterion of accuracy after approximately 35 training sessions. WAY 100635 (2.5-10 micromol/kg) produced a dose-dependent increase in WAY 100635-appropriate responding, with a mean effective dose of 3.44 micromol/kg, whereas saline or pindolol (5-25 micromol/kg) administration resulted in 0% drug lever responding. Pretreatment with the 5-HT(1A) agonists 8-OH-DPAT or LY 293284 did not modify the WAY 100635 curve, but pretreatment with the selective dopamine D(4) antagonists sonepiprazole or A-381393 completely blocked the cue. These results indicate that the discriminative stimulus effect produced by WAY 100635 is mediated by activation of dopamine D(4) receptors.

01 Apr 2004·PsychopharmacologyQ3 · MEDICINE

Aripiprazole (OPC-14597) fully substitutes for the 5-HT 1A receptor agonist LY293284 in the drug discrimination assay in rats

Q3 · MEDICINE

Article

Author: Marona-Lewicka, Danuta ; Nichols, David E.

RATIONALE:

Aripiprazole (OPC-14597) is a novel atypical antipsychotic drug with a low incidence of side effects. The therapeutic action of aripiprazole has been attributed to its unique agonist/antagonist effects at D(2) dopamine receptors; however, aripiprazole also has significant in vitro affinity at 5-HT(1A) receptors.

OBJECTIVES:

The 5-HT(1A) agonist property of aripiprazole has so far not been evaluated in any in vivo assay.

METHODS:

Thirteen male Sprague Dawley rats trained to discriminate the 5-HT(1A) agonist LY 293284 (75 nmol/kg) from saline, using a fixed ratio (FR) 50 schedule of food-reinforcement in a two-lever operant-conditioning task, were used to evaluate the behavioral effect of aripiprazole at 5-HT(1A) receptors.

RESULTS:

Aripiprazole fully mimicked LY 293284 in a drug-discrimination assay with an ED(50) of 1.39 micromol/kg (0.62 mg/kg). In combination tests, aripiprazole did not block the LY 293284 cue but at 8.92 micromol/kg (4 mg/kg) significantly reduced the response rate by lowering the threshold for induction of the 5-HT syndrome produced by the training dose of LY 293284. Moreover, the selective 5HT(1A) receptor antagonist WAY 100635 was able to block the substitution of aripiprazole in LY-293284 trained rats.

CONCLUSION:

Although the efficacy of aripiprazole against the positive symptoms of schizophrenia may be related to its dopamine receptor interactions, it seems possible that its atypical profile may derive, at least in part, from its 5-HT(1A) agonist effect, rather than from unusual D(2) receptor properties.

01 Oct 2002·PsychopharmacologyQ3 · MEDICINE

Re-evaluation of lisuride pharmacology: 5-hydroxytryptamine 1A receptor-mediated behavioral effects overlap its other properties in rats

Q3 · MEDICINE

Article

Author: Marona-Lewicka, Danuta ; Nichols, David E. ; Kurrasch-Orbaugh, Deborah M. ; Selken, Jennifer R. ; Lisnicchia, Joshua G. ; Cumbay, Medhane G.

RATIONALE:

There is substantial evidence that lisuride can produce effects linked to 5-HT(1A) receptor occupancy. Nevertheless, this action has generally been ignored in the mechanism of action of lisuride, in favor of an exclusive role for dopamine receptors in considering its antiparkinsonian effects, or an exclusive role of 5-HT(2A/2C) receptor activation in hallucinogenesis. These conclusions are surprising when one considers that the potent interaction of lisuride with 5-HT(1A) receptors has been demonstrated in several different laboratories and that activation of 5-HT(1A) and 5-HT(1B) receptors can modulate dopaminergically mediated responses.

OBJECTIVE:

The lack of full substitution of lisuride for lysergic acid diethylamide (LSD) in drug discrimination experiments and induction of a pronounced 5-HT syndrome by this compound at relatively low doses convinced us to execute two series of experiments that might explain the primary mechanism responsible for lisuride-mediated biological effects and its paradoxical classification as a dopamine agonist in the literature.

RESULTS:

In drug discrimination studies, lisuride fully mimicked the 5-HT(1A) agonist LY 293284, only partially substituted for LSD and DOI, and failed to substitute for (+)-amphetamine. Lisuride produced a significant dose-related increase in flat body posture, forepaw treading, and lower-lip retraction which reflect a modulation of behavior by action at central 5-HT(1A) receptors. Only pMPPI [4-iodo-N-[2-[4-(methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridynyl-benzamide hydrochloride], a selective 5-HT(1A) antagonist, was effective in inhibiting all 5-HT syndrome behaviors produced by lisuride, whereas pMPPI was without effect on any behavior induced by LSD. Lisuride dose dependently decreased body temperature in rats with a potency similar to that of the selective 5-HT(1A) agonist LY 293284. The hypothermic effect of lisuride was prevented by pre-injection of pMPPI, but not by ketanserin or haloperidol.

CONCLUSION:

We have demonstrated that the behavioral effects of low doses of lisuride are clearly mediated by stimulation of 5-HT(1A) receptors.

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