R. Bhat et al. / Bioorg. Med. Chem. Lett. 23 (2013) 5011–5013
5013
Nonspecific binding was determined in the presence of 10
haloperidol.
l
M
to have low nanomolar affinity for
r
receptors. The linker chain
length between the two hydrophobic regions of the molecule and
aryl substitution was important for deciding the subtype selectiv-
ity of the ligands whereas the alkylamine ring size was important
for the receptor affinity. In this study, 8a was identified as a com-
Commercially available benzo[d]thiazol-2(3H)one (3, Scheme 1)
was treated with dibromoalkane followed by aminocycloalkanes
under base catalyzed conditions to give analogue 5a–f (Scheme 1).
6-Acyl benzothiazolone intermediates (6a & b; Scheme 1) were
synthesized by Friedel–Crafts acylation of benzo[d]thiazol-
2(3H)one followed by reduction (acyl to alkyl) which led to regio-
specific 6-alkyl derivatives (9a & b; Scheme 1). The acyl/alkyl
derivatives were then treated with dibromoalkane and further
treated with aminocycloalkane under base catalyzed conditions
to give the analogues (8a–j and 11a–g; Scheme 1). Hydrochloride
salts of the compounds were prepared for biological testing.
Benzo[d]thiazol-2(3H)-one analogues (5a–d; Table 1) were syn-
thesized to investigate the effect of spacer length between
benzo[d]thiazol-2(3H)-one and azepane ring by varying it from
three to six methylene units. All the derivatives displayed good
affinity towards both receptor subtypes. The shorter chain ana-
pound with high affinity for
ity over -2 subtype.
r-1 subtype and appreciable selectiv-
r
Acknowledgments
This study was supported by grants from the National Institute
of Drug Abuse (DA023205 and DA013978) and the National Insti-
tute of General Medicine (GM014932). This investigation was con-
ducted in a facility constructed with support from research
facilities improvement program number C06 RR-13503-01 from
the National Center for Research Resources, National Institutes of
Health.
logues (5a & 5b; Table 1) demonstrated high
and 3.2 nM, respectively) and moderate selectivity (43- and
31-fold, respectively) versus the -2 subtype. In order to study the
importance of aryl substitution along with varying spacer lengths
on receptor binding, several aryl substituted (propionyl/butyryl)
r-1 affinity (Ki 4.1
Supplementary data
r
Supplementary data associated with this article can be found,
r
analogues were synthesized with spacer length varying from two
to six methylene units. Analogues with a propionyl/butyryl substi-
tution at the aryl ring and a shorter chain length (8a, 8b & 8g;
References and notes
Table 1) exhibited higher affinity for
logues with propionyl substitution had highest
exhibited by compound 8a ( -1 Ki = 4.5 nM). Placing a propionyl
group at the sixth position of benzothiazolone ring slightly im-
proved the affinity and selectivity of the compounds for -1 sub-
r
-1 subtype. However, ana-
r
-1 preference as
r
r
type as compared to its non-substituted analogue. Generally,
reduction of the aryl acyl moiety led to a slightly increased affinity
at both the receptor subtypes (11a–g; Table 1). However, the in-
creased affinity came at the expense of subtype selectivity. The
best analogues (11a & 11b; Table 1) of this series of compounds
exhibited a lower selectivity for
r-1 subtype as compared to their
corresponding analogues (8a & 8b; Table 1) with benzylic ketone
functionality. In order to elucidate the importance of ring size on
r
receptor affinity and selectivity some analogues were synthe-
sized in which the seven-membered azepane ring was replaced
with a five membered pyrrolidine or eight membered octylamine
ring. When the ring size was increased (5f; Table 1) the compound
still retained good affinity for
r-1 subtype (Ki = 9.7 nM) however it
lost affinity at -2 subtype (Ki = 716 nM). Decreasing the ring size
r
had a detrimental effect on the affinity of the compounds (5e & 8f;
Table 1) for both the receptor subtypes as well as their selectivity
over
Increase in linker arm length (from n = 2 to 5), reflects marginal
change in affinity at -1 subtype and significant increase in affinity
for the -2 subtype; (2) Modification of aryl substitution from pro-
pyl (1) to propionyl (8a) results in a dramatic decrease in -2 affin-
ity with a marginal change in -1 affinity; (3) Reduced affinity for
both receptor subtypes when the azepane ring (8a) is replaced
r-2 subtype. Some trends observed during the SAR study—(1)
r
r
r
r
r
with a pyrrolidine ring as demonstrated by 5e and 8f.
In Summary, we have reported the synthesis and SAR study
around the linker length, aromatic substitution and alkylamine
ring size of some
r receptor ligands based on the benzo[d]thia-
zol-2(3H)one chemotype. Several of these compounds were shown
Bhat, Rohit
