Effects of dopamine transporter selective 3-phenyltropane analogs on locomotor activity, drug discrimination, and cocaine self-administration after oral administration.
Several studies suggest that a dopamine transporter uptake inhibitor that has a slower onset and longer duration of action than cocaine in animal behavioral measures and decreases cocaine self-administration would be useful as an indirect dopamine agonist pharmacotherapy to treat cocaine addiction. In the present study, we compared five 3-phenyltropane analogs administered orally in locomotor activity in mice and drug discrimination in rats to gain information concerning relative potency, onset, and duration of action. The compounds were also evaluated for reduction of cocaine self-administration in rats after oral administration. In general, the compounds had a slower onset of action than cocaine and reduced cocaine self-administration. 3beta-(4-Chlorophenyl)-2beta-(3-(4'-methylphenyl)-isoxazol-5-yl)tropane (RTI-336) was the most potent in locomotor activity and drug discrimination; it was less stimulatory than cocaine in the first hour and had the slowest onset and longest duration of action. It also reduced self-administration of two infusion doses of cocaine in the rat.
Carroll
F Ivy
FI
Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USA. fic@rti.org
Fox
Barbara S
BS
Kuhar
Michael J
MJ
Howard
James L
JL
Pollard
Gerald T
GT
Schenk
Susan
S
D000284:Administration, Oral; D000818:Animals; D019970:Cocaine-Related Disorders / Q000523:psychology*; D003216:Conditioning, Operant / Q000187:drug effects; D003463:Cues; D004192:Discrimination, Psychological / Q000187:drug effects*; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005793:Generalization, Psychological / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011955:Receptors, Drug / Q000187:drug effects; D012646:Self Administration; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000494:pharmacology*
C506585:3beta-(4-chlorophenyl) tropane-2beta-(3-(4'-methylphenyl) isoxazol-5-yl) hydrochloride; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D004791:Enzyme Inhibitors; D007473:Ion Channels; D011955:Receptors, Drug; D014326:Tropanes