Synthesis, monoamine transporter binding properties, and behavioral pharmacology of a series of 3beta-(substituted phenyl)-2beta-(3'-substituted isoxazol-5-yl)tropanes.
Several 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine. All compounds showed high affinity for the DAT. The IC(50) values ranged from 0.5 to 26 nM. With the exception of 3e and 3f, which have no substituent on the 2beta-(1,2-isoxazole) ring, all compounds were selective for the DAT relative to the 5-HTT and NET. No compound showed death when dosed at 100 mg/kg; however, most compounds did show signs typical of dopamine activity. The ED(50) values for 2beta-(1,2-isoxazoles) that caused locomotor stimulation ranged from 0.2 to 12.8 mg/kg. Most compounds showed slower on-set and longer duration of action relative to cocaine. Surprisingly, 3beta-(4-methylphenyl)-2beta-[3-(4'-chlorophenyl)isoxazol-5-yl]tropane (3p) and 3beta-(4-methylphenyl)-2beta-[3-(4'-methylphenyl)isoxazol-5-yl]tropane (3r) did not produce significant increases in locomotor activity. In the cocaine discrimination test, all analogues showed full or at least 50% generalization with the exception of 3p, which did not show generalization. Importantly, both the locomotor activity and the cocaine discrimination ED(50)values were correlated with the DAT binding but not 5-HTT and NET binding. This provides further support for the dopamine hypothesis of cocaine abuse. High DAT affinity and selectivity, increased locomotor activity with slow onset and long duration of action, and generalization to cocaine shown by the 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes are properties thought necessary for a pharmacotherapy for treating cocaine abuse.
Carroll
F Ivy
FI
Chemistry and Life Sciences, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Pawlush
Neil
N
Kuhar
Michael J
MJ
Pollard
Gerald T
GT
Howard
James L
JL
D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism*; D003042:Cocaine / Q000494:pharmacology; D004193:Discrimination Learning / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins; D005793:Generalization, Psychological; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011485:Protein Binding; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D015306:Biogenic Monoamines; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007555:Isoxazoles; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D014326:Tropanes; D003042:Cocaine