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.
authors.affiliation: University of North Texas Health Science Center, Department of Pharmacology and Neuroscience, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Rangel-Barajas
authors.affiliation: University of North Texas Health Science Center, Department of Pharmacology and Neuroscience, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA.
authors.forename: Maninder
authors.initials: M
authors.lastname: Malik
authors.affiliation: Radiochemistry Laboratory, Neurology Department, University of Pennsylvania School of Medicine, Chemistry Building, 231 S. 34th Street, Philadelphia, PA 19104, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Mach
authors.affiliation: University of North Texas Health Science Center, Department of Pharmacology and Neuroscience, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107, USA. Electronic address: robert.luedtke@unthsc.edu.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Luedtke
mesh_terms: D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000633:toxicity; D000818:Animals; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D002461:Cell Line, Transformed; D018491:Dopamine Agonists / Q000737:chemistry / Q000627:therapeutic use*; D018492:Dopamine Antagonists / Q000737:chemistry / Q000494:pharmacology; D054333:Drug Partial Agonism; D019416:Head Movements / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000633:toxicity
chemical_list: D001381:Azepines; D001549:Benzamides; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C000603940:N-(4-(4-(2-methoxyphenyl)-1,4-diazepan-1-yl)butyl)-4-(thiophen-3-yl)benzamide; D010879:Piperazines; D050637:Receptors, Dopamine D3; D017366:Serotonin Receptor Agonists; C543148:WC10 compound; C543147:WC44 compound; C585146:WW-III-55; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine
keywords: 5-HT2 receptor agonist; Antipsychotic; D3 dopamine receptors; DOI; Hallucinogenesis; Head twitch response