Profiling of LINS01 compounds at human dopamine D2 and D3 receptors

Article abstract of DOI:10.1007/s12039-019-1694-6

Abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, especially in the limbic areas, making them very attractive to designing drugs with synergistic and/or additive effects. The roles of these systems to treat schizophrenia, drug addiction, Parkinson’s and Alzheimer’s diseases, among others are widely known. The LINS01 compounds were previously reported as histamine H₃ receptor (H₃R) antagonists and some of them are under evaluation in rodent memory models. Considering their pharmacological potential and similarities to literature dopamine D₂ receptor (D₂R) and dopamine D₃ receptor (D₃R) ligands, this work aimed to evaluate these compounds as ligands these receptors by using [³H]spiperone displacement assays. A set of 11 compounds containing the dihydrobenzofuranyl-piperazine core with substituents at 5-position of dihydrobenzofuran ring and at the piperazine nitrogen was examined. The compounds showed low to moderate affinities at both, D₂R and D₃R. N-Phenyl compounds LINS01005 (1d), LINS01011 (1h), LINS01012 (1i) and LINS01016 (1k) showed the highest affinities in the set to D₃R (K_i 0.3–1.5 μM), indicating that N-phenylpiperazine moiety increases the affinity to this receptor subtype with some selectivity, since they showed lower affinities to D₂R (K_i 1.3–5.5 μM). With the LINS01 compounds showing moderate binding affinity, new lead structures for optimization with regards to combined H₃R and D₂R/D₃R-ligands are provided. Graphic abstract: Histamine and dopamine neuronal pathways display interesting overlapping in the CNS, and thus LINS01 compounds previously reported as histamine H₃ receptor antagonists were evaluated as dopamine D₂R and D₃R ligands. The compounds showed micromolar affinities to both receptors[Figure not available: see fulltext.].

Full text of DOI:10.1007/s12039-019-1694-6

J. Chem. Sci.
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REGULAR ARTICLE
Profiling of LINS01 compounds at human dopamine D2 and D3
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Abstract. H i s t a m i n e a n d d o p a m i n e n e u r o n a l p a t h w a y s d i s p l a y i n t e r e s t i n g o v e r l a p p in g i n t h e C NS , e s p e-
c ia l l y i n t h e l i m b i c a r e a s , m a k i n g t h e m v e r y a t t r a c t i v e t o d e s i g n i n g d r u g s w i t h s y n e r g i s t ic a n d /o r a dd i t iv e
e f f e ct s. T h e r o l e s o f t h e s e s y s t e m s t o t r e a t s c h i z o p h r e n i a , d r u g a d d ic t i o n , P a r k in s o n ’ s a n d A l z h e i m e r’ s
d i s ea s e s , a m o n g o t h e rs a r e w i d e l y k n o w n . T h e L I N S 0 1 c o m p o u n d s w e r e p r e v i o u s l y r e p o r t e d a s h i s t a m i n e H
r e c ep t o r ( H R ) a n t a g o n i s t s a n d s o m e o f t h e m a r e u n d e r e v a lu a ti o n i n r o d e n t m e m o r y m o d e ls . C o n s i d e ri n g
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t h ei r p h a r m a c o l o g i c a l p o t e n t i a l a n d s i m i l a r i t i e s t o l it e r a tu r e d o p a m in e D r e c e p t o r ( D R ) a n d d o p a m i n e D
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c o r e w i t h s u b s t i t u e n t s a t 5 - p o s i t i o n o f d i h y d r o b e n z o f u r a n r i n g a n d a t t h e p i p e r a z i n e n i t r o g e n w a s e x am i ne d .
T h e c o m p o u n d s s h o w e d l o w t o m o d e r a t e a f fi n i t ie s a t b o t h , D R a n d D R . N- P h e n y l c o m p o u n d s L I N S 0 1 00 5
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( 1d) , L I N S 0 1 0 1 1 (1h) , L I NS 0 1 0 1 2 ( 1i) a n d L I N S 0 1 0 1 6 ( 1k) s h o w e d t h e h i g h e s t a f fi n it i e s i n t h e s e t t o D R
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s h o w i n g m o d e r a t e b i n d i n g a f fi n i t y , n e w l e a d s t r u c t u r e s f o r o p t i m i z a t io n w i t h r e g a r d s t o c o m b in e d H R a nd
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Keywords. A n t i h i s t a m i n e ; d o p a m i n e r e c e p t o r l ig a n d ; D 2 r e c e p t o r ; D 3 r e c e p t o r .
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D R /D R .
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J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 : 5
P
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6
5
h a l o p e r i d o l ( 1 0 lM ) . I n h i b i t io n w a s c a l c u l a t e d a s r es i du al
o f s p e c i fi c b i n d i n g o f [ H ] s p i p e r o n e i n p r e s e n c e o f c om -
3
p o u n d r e l a t i v e t o s p e c ifi c b i n d i n g i n t h e a b s e n c e o f i nh i -
b i t o r . F o r a f fi n it y m e a s u r e m e n ts , t h e s a m e p r o c e du r e a s
a b o v e w a s u s e d b u t i n c l u d i n g a t it r a ti o n p a t t e r n o f t he
i n v e s t i g a t e d l ig a n d s ( 0 .0 1 – 1 0 0 ,0 0 0 n M , fi n a l c o nc en t r a-
t io n ) . T h e fi n a l l y d e t e r m i n e d s p e c ifi c b i n d i n g w a s a na l yz ed
b y n o n - l i n e a r l e a s t - s q u a r e fi t ti n g t o a f o u r - p ar a m e te r
cariprazine
BP897
l o g i s t ic e q u a ti o n . C o n v e r s i o n o f t h e d e t e r m in e d I C t o Ki
5 0
FAUC365
2
5
v a l u e s w a s p e r f o r me d a s d e s c r ib e d e l s e w h e r e .
Figure 2. L i g a n d s o f D R a n d D R r e p o r t e d i n t h e
2
3
l
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.
3. Results and Discussion
c o m p o u n d s w e r e c h e c k e d f o r p u r i t y t h r o u g h c h ro m a t o g r a -
p h y a n d c o ns i d e r ed a d e q u a t e w h e n p u r i t y w a s [9 5 % .
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2 . 2 Binding assays on D2R and D3R
M e m b r a n e s f r o m C H O c e l l s s t a b l y e x p r e s s i n g e i t h e r t h e
s h o r t t r a n s cr i p t o f D r e c e p t o r s o r D r e c e p t o r s w e r e p r e -
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p a r e d a s d e sc r i b e d p r e v i o u s l y . F o r i n h i b i t i o n s c r e e n i n g ,
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[ 50 m M T R I S ( p H = 7 . 4 ) 1 2 0 m M N a C l , 5 m M K C l ,
1 m M C a C l a n d 1 m M M g C l ] . A ft e r a n i n c u b a t i o n p e r io d
LINS010XX
R1 = H, Me, Allyl, Ph, Bn
R2 = H, Cl, Me, MeO, tBu, Ph
2
2
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b y t h r e e w a s h - s t ep s u s i n g c o l d d e m i n e r a l i z e d w a t e r ( a p -
p ro x . 1 m L / sa m p l e ). T h e w o r k u p f o r s c i n t i l l a t i o n - c o u n t i n g
Scheme 1. R e a g e n ts a n d c o n d i ti o n s . ( a ) A l l y l b r o m i d e ( 2
e q . ) , K C O ( 2 e q . ) , a c e t o n e , 6 0 °C , 2 – 4 h ; ( b ) D M F , M W
2
3
2 0 0 °C ( 3 0 0 p s i , 3 0 0 W ) , 1 , 5 h ; ( c ) I ( 1 .1 e q . ) , w a t er o r
2
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f ol l o w ed t h e s t a n d a rd p r o c e d u r e d e s c r i b e d b e fo re . N o n -
E t O H / w a t e r , r.t., 4 – 6 h ; ( d ) K C O ( 1 .2 e q . ) , T H F , r efl ux ,
2
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5
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J. Chem. Sci.
( 2 0 2 0 ) 1 3 2 :5
Table 1. S c r e e n i n g o f t h e c o m p o u n d s L I N S 0 1 t o w a r d s i n h i b i ti o n a n d a f fi n it y a t t h e h u m a n d o p a m i n e D R a n d D R .
2
3
% i n h i b i ti o n ( 1 0 lM ) S D ( n )
Ki ( lM ) [ 9 5 % C I ]
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1d ( L I N S 01 00 5 )
1e ( L I N S 0 1 0 0 7 )
1f ( L I N S 0 1 0 0 8 )
1g ( L I N S 0 10 1 0 )
1h ( L I N S 01 01 1 )
1i ( LI N S 0 10 1 2 )
1j ( L I N S 0 1 0 1 6 )
1k ( L I N S 01 01 7 )
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1 . 5 1 3 . 9 ( 1 5 )
3 3 . 6 9 . 7 ( 1 5 )
3 4 . 1 1 0 . 5 ( 1 5 )
1 0 . 3 1 0 . 9 ( 1 5 )
1 1 . 1 1 1 . 7 ( 1 5 )
1 2 . 9 1 2 . 7 ( 1 5 )
4 4 . 0 3 . 6 ( 6 )
4 5 . 1 4 . 2 ( 6 )
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6 2 . 3 1 4 . 4 ( 1 5 )
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3 1 . 7 8 . 5 ( 1 5 )
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2 . 4
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2 . 6
[ 1 .2 – 6 . 1 ]
2 . 4
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1 .5
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0 .8 9
[ 0 .4 5– 1 .7 5 ]
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[ 0 .6 – 3 . 0 ]
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4. Conclusions
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6 . C o r r e a M F a n d F e r n a n d e s J P S 2 0 1 5 H i s t a m i n e H 4
r e c e p t o r l ig a n d s : F u t u r e a p p l i c a t io n s a n d s t a t e o f a rt
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A n ta g o n i s ts a s P o t e n t i a l T h e r a p e u t i c s f o r t h e T re at -
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Supplementary Information (SI)
1 2 . E l le n b r o e k B A 2 0 1 3 H i s t a m i n e H 3 r e c e p t o r s , t he
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v e r s u s D 2 R e c e p t o r S u b t y p e S e l e c t i v i ty J. Med. Chem.
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