Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice

II. Effects of D3 dopamine receptor selective compounds

Claudia Rangel-Barajas, Maninder Malik, Robert H. Mach, Robert T. Luedtke

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

Original languageEnglish
Pages (from-to)179-190
Number of pages12
JournalNeuropharmacology
Volume93
DOIs
StatePublished - 1 Jan 2015

Fingerprint

Dopamine D3 Receptors
Inbred DBA Mouse
Head
Pharmacology
Dopamine D2 Receptors
Inhibitory Concentration 50
Rotarod Performance Test
Hallucinogens
Hypnotics and Sedatives
Antipsychotic Agents
N-(4-(4-(2-methoxyphenyl)-1,4-diazepan-1-yl)butyl)-4-(thiophen-3-yl)benzamide

Keywords

  • 5-HT2 receptor agonist
  • Antipsychotic
  • D3 dopamine receptors
  • DOI
  • Hallucinogenesis
  • Head twitch response

Cite this

@article{b055734956b947f8916fb6d4e2dcd6b2,
title = "Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice: II. Effects of D3 dopamine receptor selective compounds",
abstract = "We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95{\%}, while LAX-4-136 administration resulted in a 50{\%} reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.",
keywords = "5-HT2 receptor agonist, Antipsychotic, D3 dopamine receptors, DOI, Hallucinogenesis, Head twitch response",
author = "Claudia Rangel-Barajas and Maninder Malik and Mach, {Robert H.} and Luedtke, {Robert T.}",
year = "2015",
month = "1",
day = "1",
doi = "10.1016/j.neuropharm.2014.10.030",
language = "English",
volume = "93",
pages = "179--190",
journal = "Neuropharmacology",
issn = "0028-3908",
publisher = "Elsevier Ltd",

}

Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice : II. Effects of D3 dopamine receptor selective compounds. / Rangel-Barajas, Claudia; Malik, Maninder; Mach, Robert H.; Luedtke, Robert T.

In: Neuropharmacology, Vol. 93, 01.01.2015, p. 179-190.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Pharmacological modulation of abnormal involuntary DOI-induced head twitch response movements in male DBA/2J mice

T2 - II. Effects of D3 dopamine receptor selective compounds

AU - Rangel-Barajas, Claudia

AU - Malik, Maninder

AU - Mach, Robert H.

AU - Luedtke, Robert T.

PY - 2015/1/1

Y1 - 2015/1/1

N2 - We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

AB - We recently reported on the characterization of the hallucinogen 2,5-dimethoxy-4-methylamphetamine's (DOI) ability to elicit a head twitch response (HTR) in DBA/2J mice and the ability of D2 vs. D3 dopamine receptor selective compounds to modulate that response. For these studies, the ability of D3 vs. D2 dopamine receptor selective compounds to attenuate the DOI-dependent HTR was examined. WC 10, a D3 dopamine receptor weak partial agonist with 40-fold binding selectivity for D3 vs. D2 dopamine receptors, produced a dose-dependent decrease in the DOI-induced HTR (IC50 = 3.7 mg/kg). WC 44, a D3 receptor selective full agonist, also inhibited the DOI-induced HTR (IC50 = 5.1 mg/kg). The effect of two D3 receptor selective partial agonists, LAX-4-136 and WW-III-55, were also evaluated. These analogs exhibit 150-fold and 800-fold D3 vs. D2 binding selectivity, respectively. Both compounds inhibited the HTR with similar potency but with different maximum efficacies. At 10 mg/kg WW-III-55 inhibited the HTR by 95%, while LAX-4-136 administration resulted in a 50% reduction. In addition, DOI (5 mg/kg) was administered at various times after LAX-4-136 or WW-III-55 administration to compare the duration of action. The homopiperazine analog LAX-4-136 exhibited greater stability. An assessment of our test compounds on motor performance and coordination was performed using a rotarod test. None of the D3 dopamine receptor selective compounds significantly altered latency to fall, suggesting that these compounds a) did not attenuate the DOI-dependent HTR due to sedative or adverse motor effects and b) may have antipsychotic/antihallucinogenic activity.

KW - 5-HT2 receptor agonist

KW - Antipsychotic

KW - D3 dopamine receptors

KW - DOI

KW - Hallucinogenesis

KW - Head twitch response

UR - http://www.scopus.com/inward/record.url?scp=84923587070&partnerID=8YFLogxK

U2 - 10.1016/j.neuropharm.2014.10.030

DO - 10.1016/j.neuropharm.2014.10.030

M3 - Article

VL - 93

SP - 179

EP - 190

JO - Neuropharmacology

JF - Neuropharmacology

SN - 0028-3908

ER -