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

We previously reported (J. Med, Chem. 1993, 36, 1188-1193) that change s 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 som e cases opposite, changes in affinity for sites on the DA transporter labeled by [H-3]BTCP and [H-3]-cocaine. These results suggested that t he radioligands label different sites on the transporter. In the prese nt study, we extend the structure-activity relationships (SAR) of BTCP by studying the binding characteristics of a series of N,N-disubstitu ted 1-(a-benzo[b]thienyl) cyclohexylamines 7-32 at the DA transporter. Cyclohexyl was selected as opposed to other ring sizes since it corre sponds to BTCP. The binding results indicate that a considerable degre e of structural variation is permitted for the N-substituents, while s till retaining nanomolar affinity for sites on the transporter (studie d 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 di fferent and distinct binding sites. In general, and up to a point, inc reasing the size and lipophilicity of the N substituents resulted in i mprovements in binding but appeared to have less predictable effects o n DA-uptake inhibition (as measured in rat brain synaptosomes). The bi nding of these compounds to sites labeled by [H-3]BTCP appeared to cor relate best with IC50 for DA-uptake inhibition. To our surprise, the m onoalkyl N-substituted BTCP derivatives displayed the highest affinity for the DA transporter of all the compounds in this series. For examp le, the N-(cyclopropylmethyl) derivative 14 displayed IC50's = 23 nM ( [H-3]cocaine) and 1 nM ([H-3]-BTCP), and the N-butyl derivative 10 sho wed IC50's = 60 nM ([H-3]cocaine) and 0.3 nM ([H-3]BTCP). BTCP exhibit ed IC50's of 39 nM ([H-3]cocaine) and 5 nM ([H-3]BTCP) in this assay. The observation that N,N-dibutyl derivative 31 exhibited low ratios of IC50 [H-3] cocaine/IC50 DA reuptake and IC50 [H-3]BTCP/IC50 DA reupta ke suggests that it may be a potential candidate for cocaine antagonis m 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 phencyclidine receptors coupled with their high affinity and range of selectivities at the DA transporter identifies many of them as useful tools for prob ing the mode of action of BTCP at this site.