3β-(4-methylphenyl)-2β-[3-(4-chlorophenyl)isoxazol-5-yl]tropane (RTI-371) is a phenyltropane derived drug which acts as a potent and selective dopamine reuptake inhibitorin vitro, yet unusually for this class of compound, both RTI-371 and the closely related compound RTI-370 failed to produce locomotor stimulation in mice. In addition to this, in drug substitution tests RTI-370 weakly generalized to cocaine whereas RTI-371 did not generalize at all.
This phenomenon has also been observed for other dopamine reuptake inhibitors from other classes. It may be caused by lack of BBB penetration, or interactions at alternative receptor sites. Recently the second of these hypotheses was suggested for this compound when it was discovered that RTI-371 also acts as a positive allosteric modulator of the hCB1 human cannabinoid receptor.
^Navarro HA, Howard JL, Pollard GT, Carroll FI. Positive allosteric modulation of the human cannabinoid (CB) receptor by RTI-371, a selective inhibitor of the dopamine transporter. Br J Pharmacol. 2009 Apr;156(7):1178-84. doi:10.1111/j.1476-5381.2009.00124.xPMID 19226282