Structure-activity relationships at the monoamine transporters and a receptors for a novel series of 9-[3-(cis-3,5-dimethyl-1-piperazinyl)-propyl]carbazole (rimcazole) analogues

9-[3-(cis-3,5-Dimethyl-1-piperazinyl)propyl]carbazole (rimcazole) has been characterized as a a receptor antagonist that binds to the dopamine transpo rter with moderate affinity (K-i = 224 nM). Although the binding affinities at the dopamine transporter of rimcazole and cocaine are comparable, rimca zole only depressed locomotor activity in mice and antagonized the stimulan t effects produced by cocaine. The neurochemical mechanisms underlying the attenuation of cocaine's effects are not understood, although interaction a t a low affinity site/state of the dopamine transporter has been suggested. To explore further this class of compounds, a series of rimcazole analogue s was designed and synthesized. Displacement of [H-3]WIN 35,428 binding at the dopamine transporter in rat caudate-putamen revealed that aromatic subs titutions on rimcazole were not well tolerated, generally, with significant reductions in affinity for the 3,6-dibromo (5; K-i = 3890 nM), 1,3,6-tribr omo (6; K-i = 30300 nM), 3-amino (8; K-i = 2400 nM), and 3,6-dinitro (9; K- i = 174000 nM) analogues. The N-phenylpropyl group was the only terminal pi perazine nitrogen substituent that retained moderate affinity at the dopami ne transporter (11; K-i = 263 nM). Analogues in which the carbazole ring wa s replaced with a freely rotating diphenylamine moiety were also prepared. Although the diphenylamino analogue in which the terminal piperazine nitrog en was unsubstituted, as in rimcazole, demonstrated relatively low binding affinity at the dopamine transporter (24; K-i = 813 nM), the N-phenylpropyl analogue was found to have the highest affinity for the dopamine transport er within the series (25; K-i = 61.0 nM). All of the analogues that had aff inity for the dopamine transporter inhibited [H-3]-dopamine uptake in synap tosomes, and potencies for these two effects showed a positive correlation (r(2) = 0.7731, p = 0.0018). Several of the analogues displaced [H-3]paroxe tine from serotonin transporters with moderate to high affinity, with the N -phenylpropyl derivative (11) having the highest affinity (K-i = 44.5 nM). In contrast, none of the analogues recognized the norepinephrine transporte r with an affinity of <1.3 mu M . Binding affinities for sigma(1) and sigma (2) receptors were also determined, and several of the compounds were more potent than rimcazole with affinities ranging from 97 nM to >6 mu M at ol s ites and 145 to 1990 nM sigma(2) sites. The compound with the highest affin ity (25) at ol sites was also the compound with highest affinity at the dop amine transporter. These novel rimcazole analogues may provide important to ols with which to characterize the relationship between the low affinity si te or state of the dopamine transporter, sigma receptors, and their potenti al roles in modulating cocaine's psychostimulant actions.