Further studies of the structure-activity relationships of 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine. Synthesis and evaluation of 1-(2-benzo[b]thienyl)-N,N-dialkylcyclohexylamines at dopamine uptake and phencyclidine binding sites

Abstract

We previously reported (J. Med. Chem. 1993, 36, 1188-1193) that changes to the ring size of the piperidine and cyclohexyl rings of the high-affinity and selective dopamine (DA)-uptake inhibitor 1-[1-(2-benzo[b]thienyl)cyclohexyl]piperidine (BTCP, 2) caused different, and in some cases opposite, changes in affinity for sites on the DA transporter labeled by [3H]BTCP and [3H]-cocaine. These results suggested that the radioligands label different sites on the transporter. In the present study, we extend the structure-activity relationships (SAR) of BTCP by studying the binding characteristics of a series of N,N-disubstituted 1-(2-benzo[b]thienyl)cyclohexylamines 7-32 at the DA transporter. Cyclohexyl was selected as opposed to other ring sizes since it corresponds to BTCP. The binding results indicate that a considerable degree of structural variation is permitted for the N-substituents, while still retaining nanomolar affinity for sites on the transporter (studied in rat forebrain homogenates). As observed in our earlier study, the differential effects of structural change on binding to sites on the DA transporter labeled by these radioligands suggests that they are different and distinct binding sites. In general, and up to a point, increasing the size and lipophilicity of the N substituents resulted in improvements in binding but appeared to have less predictable effects on DA-uptake inhibition (as measured in rat brain synaptosomes). The binding of these compounds to sites labeled by [3H]BTCP appeared to correlate best with IC50 for DA-uptake inhibition. To our surprise, the monoalkyl N-substituted BTCP derivatives displayed the highest affinity for the DA transporter of all the compounds in this series. For example, the N-(cyclopropylmethyl) derivative 14 displayed IC50's = 23 nM ([3H]cocaine) and 1 nM ([3H]-BTCP), and the N-butyl derivative 10 showed IC50's = 60 nM ([3H]cocaine) and 0.3 nM ([3H]-BTCP). BTCP exhibited IC50's of 39 nM ([3H]cocaine) and 5 nM ([3H]BTCP) in this assay. The observation that N,N-dibutyl derivative 31 exhibited low ratios of IC50 [3H]cocaine/IC50 DA reuptake and IC50 [3H]BTCP/IC50 DA reuptake suggests that it may be a potential candidate for cocaine antagonism studies. The effect of additional amino, amide, and aromatic groups on the N-substituents was examined, and the results are discussed. The failure of all of the compounds in this series to bind phenycyclidine receptors coupled with their high affinity and range of selectivities at the DA transporter identifies many of them as useful tools for probing the mode of action of BTCP at this site.

The Mechanism of Fenretinide (4-HPR) Inhibition of β-carotene Monooxygenase 1. New Suspect for the Visual Side Effects of Fenretinide

“…Synthesis of fenretinine was done by Alane reduction of amide based on previously described synthesis of dopamine-uptake inhibitors (He et al 1993 ) . To a fl ame-dried 15 mL round bottom fl ask was added fenretinide (6 mg, 15.3 m mol) and freshly distilled, dry tetrahydrofuran (2 mL).…”

Studies of the biogenic amine transporters. VII. Characterization of a novel cocaine binding site identified with [125I]RTI-55 in membranes prepared from human, monkey and guinea pig caudate

“…In contrast, other agents such as (29,30) and GBR12909 analogs for the rat DAT and SERT site2 . Since we had exhausted our supply of monkey caudate, we first verified that guinea pig caudate could be used in place of monkey caudate.…”

“…For the ligand-selectivity studies of the BTCP (''SH'' compounds) (29) and GBR12909 analogs (''DM'' compounds) (49), DAT binding was determined using rat caudate membranes with 50 nM paroxetine as a blocker (8) and SERT site2 binding was determined using guinea pig caudate membranes with 100 nM GBR12935 and 50 nM paroxetine as blockers. Guinea pig caudate membranes could not be used for assay of the DAT since a selective blocker of SERT site2 is not currently available.…”

Development of Novel, Potent, and Selective Dopamine Reuptake Inhibitors through Alteration of the Piperazine Ring of 1-[2-(Diphenylmethoxy)ethyl]- and 1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines (GBR 12935 and GBR 12909)

“…dopamine reuptake inhibitors, , and many others. Since the dopamine transporter seems to play an essential role in the mechanism of cocaine action in the brain, a variety of structurally diverse DAT ligands have been subjected to a number of pharmacological studies. ,− Disubstituted piperazines 1 and 2 (Chart ) proved to be among the most potent and selective DA reuptake inhibitors. − It has been hypothesized that the development of a high-affinity, low intrinsic activity partial cocaine agonist, which noncompetitively inhibits the DA reuptake but does not produces euphoria (the DA reuptake blocker type 2 , ), might be a suitable approach to treat cocaine addiction in humans. In microdialysis experiments, the slowly dissociating DAT ligand, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine ( 2 , GBR 12909), was shown to attenuate the extracellular DA (ECDA) levels enhanced by cocaine in rat striatum and nucleus accumbens…”