Synthesis of 3β-Aryl-8-azabicyclo[3.2.1]octanes with High Binding Affinities and Selectivities for the Serotonin Transporter Site

Abstract

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3 position was directly bound to the tropane ring and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.

Synthesis and structure–activity studies of benzyl ester meperidine and normeperidine derivatives as selective serotonin transporter ligands

“…Previous studies had shown these aryl groups to contribute to the high potency and selectivity at SERT observed for the meperidine ethyl ester derivatives 2a-d (Table 1) as well as a variety of piperidine and tropane derivatives. 27-30 As illustrated in Scheme 1, an initial series of normeperidine derivatives 4 were prepared from the corresponding ethyl esters 2 using 1-chloroethyl chloroformate (ACE-Cl). This two-step one-pot processs typically afforded the normeperidine derivatives 4 in 59% - 73% yield.…”

Dirhodium(II) Carbenes : The Chiral Product Cascade

“…These reports now include diastereomeric excesses of up to 97% in the dirhodium(II) octanoate catalysed cyclopropanation of styrenes and vinyl ethers with (R)-pantolactone-and (S)-lactate-substituted vinyldiazomethane 18 with (Table 1) (Davies et al, 1993c(Davies et al, , 1997a These workers (Davies et al, 1998a) have shown that appropriate choice of vinyldiazo substituent allows facile subsequent transformation of the cyclopropyl products to 2,3-dihydrofurans with high asymmetric induction. This methodology has been extended to diene systems, furans (Davies et al, 1996b) to give 8-oxabicyclo[3.2.1]octan-3-ones and pyrroles (Davies et al, 1997b) to give tropanes (Scheme 4).The fundamental reaction sequence has allowed the preparation of the oxabicycles 20-22 and a series of 2β-acyl-3β-aryltropanes 23 (Davies et al, 1994a(Davies et al, , 1996c CCOO, as in catalysts 6 (substituents varied from H, Me, and Ph; to OH, NHAc, and CF 3 ) and Kennedy et al (1990) persued the chiral prolinate derivatives 7 (Z = H). They found that enantioselectivities in the cyclopropanation of styrene with ethyl diazoacetate were less than 12% ee and 30% ee respectively.…”

Synthesis, radiolabeling and baboon SPECT imaging of 2β-carbomethoxy-3β-(3′-[123I]iodophenyl)tropane ([123I]YP256) as a serotonin transporter radiotracer

“…The PET tracer [ 11 C] (+)-McN-5652-Z has been used for several years 11 , even though its low target to background ratio limits its use to high density regions like the midbrain 12,13 . A fluorine-18 labeled analog [ 18 Based on the observations of Carroll 19 and Davies 20,21 that selectivity for 5-HTT was enhanced by unsaturated substituents on the phenyl ring and by N-demethylation (trends confirmed by preliminary results with 4′-substituted analogs 22,23 ), we synthesized a series of 3′-substituted tropane analogs and measured their binding affinity towards the three monoamine transporters. The potency (Ki, nM) of the compounds was evaluated by competition against radiolabeled ligands selective for 5-HTT, DAT, and NET in rat forebrain tissue and human cell membranes and binding selectivity was calculated as the inverse ratio of Ki values.…”