title: 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.
authors.affiliation: Laboratory of Medicinal Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892.
authors.forename: X
authors.initials: X
authors.lastname: He
authors.forename: L P
authors.initials: LP
authors.lastname: Raymon
authors.forename: M V
authors.initials: MV
authors.lastname: Mattson
authors.forename: M E
authors.initials: ME
authors.lastname: Eldefrawi
authors.forename: B R
authors.initials: BR
authors.lastname: de Costa
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D003042:Cocaine / Q000037:antagonists & inhibitors; D003514:Cyclohexylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism*; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D003514:Cyclohexylamines; D018492:Dopamine Antagonists; D010880:Piperidines; C056415:1-(1-(2-benzo(b)thienyl)cyclohexyl)piperidine; D003042:Cocaine; D010622:Phencyclidine; D004298:Dopamine