SYNTHESIS OF 2-BETA-ACYL-3-BETA-ARYL-8-AZABICYCLO[3.2.1]OCTANES AND THEIR BINDING AFFINITIES AT DOPAMINE AND SEROTONIN TRANSPORT SITES IN RAT STRIATUM AND-FRONTAL CORTEX
Hml. Davies et al., SYNTHESIS OF 2-BETA-ACYL-3-BETA-ARYL-8-AZABICYCLO[3.2.1]OCTANES AND THEIR BINDING AFFINITIES AT DOPAMINE AND SEROTONIN TRANSPORT SITES IN RAT STRIATUM AND-FRONTAL CORTEX, Journal of medicinal chemistry, 37(9), 1994, pp. 1262-1268
A novel entry to tropane analogs of cocaine was developed on the basis
of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles.
These analogs were tested:in binding to dopamine and serotonin (5-HT)
transporters in:membranes from rat striatum and frontal cortex. In all
the analogs, the aryl group at the 3-position was directly bound to t
he tropane ring (as in WIN-35,428), and methyl or ethyl ketone moietie
s were present at the a-position instead of the typical ester group. T
he series of analogs containing a 2-naphthyl group at the 3-position w
ere most potent, with K-i values < 1 nM in binding to both dopamine an
d 5-HT transporters. Although the unsubstituted 2-naphthyl analog was
nonselective at dopamine and 5-HT transport sites, other compounds:wer
e selective for either site. In general, compounds with relatively sma
ll substituents on the aromatic moiety (such as p-methyl or p-fluoro)
were relatively selective for the dopamine transporters, while a p-iso
propylphenyl derivative was selective:for the 5-HT transport sites. Th
is latter compound represents the first N-methyltropane derivative spe
cific for 5-HT transporters. Resolution of two of the most significant
analogs was achieved by HPLC on a chiral stationary phase; the active
enantiomer of a 2-naphthyl analog exhibited K-i values of <0.1 nM at
both dopamine and 5-HT transporter sites.