Interaction of cis-(6-Benzhydrylpiperidin-3-yl)benzylamine Analogues with Monoamine Transporters:  Structure−Activity Relationship Study of Structurally Constrained 3,6-Disubstituted Piperidine Analogues of (2,2-Diphenylethyl)-[1-(4-fluorobenzyl)piperidin-4-ylmethyl]amine

Abstract

To explore structure-activity relationships (SAR) of a novel conformationally constrained lead cis-3,6-disubstituted piperidine derivative derived from (2,2-diphenylethyl)-[1-(4-fluorobenzyl)piperidine-4-ylmethyl]amine (I), a series of compounds was synthesized by derivatizing the exocyclic N-atom at the 3-position of the lead. This study led to the formation of substituted phenyl and heterocyclic derivatives. All novel compounds were tested for their affinity at the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in competing for the binding of [3H]WIN 35 428, [3H]citalopram, and [3H]nisoxetine, respectively. Selected compounds were also evaluated for their activity in inhibiting the uptake of [3H]DA. The SAR results demonstrated that the nature of substitutions on the phenyl ring is important in activity at the DAT with the presence of an electron-withdrawing group having the maximum effect on potency. Replacement of the phenyl ring in the benzyl group by heterocyclic moieties resulted in the development of compounds with moderate activity for the DAT. Two most potent racemic compounds were separated by a diastereoisomeric separation procedure, and differential affinities were observed for the enantiomers. Absolute configuration of the enantiomers was obtained unambiguously by X-ray crystal structural study. One of the enantiomers, compound S,S-(-)-19a, exhibited the highest potency for the DAT (IC50 = 11.3 nM) among all the compounds tested and was as potent as GBR 12909 (1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine). However, the compound (-)-19a was more selective than GBR 12909 in binding to the DAT compared with binding to the SERT and NET. The present results establish the newly developed 3,6-disubstituted piperidine derivatives as a novel template for high-affinity inhibitors of DAT. Structurally these molecules are more constrained compared to our earlier flexible piperidine molecules and, thus, should provide more insights about their bioactive conformations.

Pharmacological modulation of GABAB receptors affects cocaine-induced seizures in mice

“…On the other hand, the release of the same monoamines is attenuated following activation of the presynaptic GABA B receptors (Bowery 1993), thus providing a possible explanation of the anticonvulsant efficacy of baclofen against cocaine seizures. Further support for this explanation is the anticonvulsant efficacy of baclofen against seizures induced by the serotonin precursor 5-hydroxytryptophan (Snodgrass 1992) and by a high dose of GBR 12909 (present study) at which non-selective inhibition of monoamine transporters is likely to occur (Kolhatkar et al 2003). High doses of cocaine also have local anesthetic actions (Reith et al 1985) that have been implicated in its convulsant effects (Stripling et al 1989).…”

“…Although there was not a wide margin between doses of (€)-baclofen that prevented seizures and doses that affected motor function, the potency separations were significant and point to a selective anticonvulsant action of this compound against cocaine. The anticonvulsant effects of (€)-baclofen appeared specific to seizures induced by the monoamine transporter inhibitors cocaine and GBR 12909 (Kolhatkar et al 2003), but not to those induced by convulsant agents that act at NMDA, GABA A or A 1 /A 2 adenosine receptors (Rogawski and Porter 1990). Finally, the GABA B receptor antagonist phaclofen potentiated the convulsant effects of the threshold dose of cocaine.…”

Further structural optimization of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine and 1,4-diazabicyclo[3.3.1]nonane derivatives by introducing an exocyclic hydroxyl group: Interaction with dopamine, serotonin, and norepinephrine transporters

“…17,18 In the current study, we wanted to explore whether introduction of an exocyclic hydroxyl group can further increase affinity of these compounds for DAT or for other monoamine transporters. We had established earlier that (−)-enantiomeric (S,S) versions of disubstituted diamines exhibited the highest potency.…”

Triple Reuptake Inhibitors as Potential Next-Generation Antidepressants: A New Hope?

“…Our next effort led to the identification of highly selective and more potent DAT inhibitors than the parent molecule GBR12909 with a promise as cocaine antagonists [86][87][88]. In subsequent efforts, with an aim to elucidate the bioactive conformation of our lead compounds, medicinal chemistry approach came to forefront in the design of conformationally rigid piperidine analogs (Figure 2), which emerged as more potent and selective at DAT than GBR12909 [89][90][91]. Further efforts led to the bioisosteric substitution of the piperidine ring with a pyran moiety resulting in the discovery of the cis-3,6-disubstituted pyran template, which became an established pharmacophore moiety of our lead TRIs, representing a unique structural class not known to any existing MAT [92].…”