Ej. Homan et al., C5-substituted derivatives of 5-OMe-BPAT: Synthesis and interactions with dopamine D-2 and serotonin 5-HT1A receptors, BIO MED CH, 7(11), 1999, pp. 2541-2548
Eight new C5-substituted derivatives of the potential atypical antipsychoti
c agent 5-methoxy-2-[N-(2-benzamidoethyl)-N-n-propylamino]tetralin (5-OMe-B
PAT, 1) have been prepared by chemical conversion of the 5-trifluoromethyls
ulfonyloxy (triflate) analogue 4 via various Stille-type cross-couplings, a
Heck reaction, and an amidation in moderate to good yields. The 5-acetyl,
5-cyano, 5-methyl, 5-(2-furyl), 5-phenyl, methyl 5-carboxylate, and the 5-c
arboxamido analogues 5-11 thus obtained, the previously disclosed 5-methoxy
, 5-hydroxy, and 5-unsubstituted analogues 1-3, and the 5-triflate analogue
4 were evaluated for their ability to compete for [H-3]-spiperone binding
to rat striatal membranes containing dopamine D-2 receptors, and their abil
ity to compete for [H-3]-8-OH-DPAT. binding to rat frontal cortex membranes
containing serotonin 5-HT1A receptors in vitro. Compounds 1-11 displayed w
eak to high affinities for dopamine D-2 receptors, with K-i-values ranging
from 550 nM for the 5-carboxamido analogue to 4.9 nM for the 5-hydroxy anal
ogue. The relative affinities of the 5-methoxy, 5-hydroxy, and 5-unsubstitu
ted analogues suggested that these compounds may bind to the same site and
in a similar way as the 5-oxygenated DPATs, with the 5-methoxy substituent
of 1 functioning as a hydrogen bond acceptor. The serotonin 5-HT1A receptor
tolerated more structural diversity at the C5-position of 1 as revealed by
the higher K-i-values of 1-11. which ranged from 60 nM for the 5-carboxami
do analogue to 1.0 nM for the 5-unsubstituted analogue. Partial least-squar
es (PLS) analysis of a set of 24 molecular descriptors, generated for each
analogue, revealed no significant correlation between the dopamine D-2 rece
ptor affinities of 1-11 and their molecular properties, supporting the view
that they may have different binding modes at this receptor subtype. A PLS
model with moderate predictability (Q(2) = 0.49) could be derived for the
serotonin 5-HT1A receptor affinities of 1-11. According to the model, a rel
atively lipophilic, nonpolar CS-substituent should be optimal for a high af
finity at this receptor subtype. (C) 1999 Elsevier Science Ltd. All rights
reserved.