Further structural optimization of cis-(6-benzhydryl-piperidin-3-yl)-benzylamine and 1,4-diazabicyclo[3.3.1]nonane derivatives by introducing an exocyclic hydroxyl group: interaction with dopamine, serotonin, and norepinephrine transporters.
Our earlier effort to develop constrained analogues of flexible piperidine derivatives for monoamine transporters led to the development of a series of 3,6-disubstituted piperidine derivatives, and a series of 4,8-disubstituted 1,4-diazabicyclo[3.3.1]nonane derivatives. In further structure-activity relationship (SAR) studies on these constrained derivatives, several novel analogues were developed where an exocyclic hydroxyl group was introduced on the N-alkyl-aryl side chain. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin (5-HT) transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. Compounds were also tested for their binding potency at the DAT by their ability to inhibit binding of [(3)H]WIN 35,428. The results indicated that position of the hydroxyl group on the N-alkyl side chain is important along with the length of the side chain. In general, hydroxyl derivatives derived from more constrained bicyclic diamines exhibited greater selectivity for interaction with DAT compared to the corresponding 3,6-disubstituted diamines. In the current series of molecules, compound 11b with N-propyl side chain with the hydroxyl group attached in the benzylic position was the most potent and selective for DAT (K(i)=8.63nM; SERT/DAT=172 and NET/DAT=48.4).
Mishra
Manoj
M
Department of Pharmaceutical Sciences, Wayne State University, Applebaum College of Pharmacy & Health Sciences, Room# 3128, Detroit, MI 48202, USA.
Kolhatkar
Rohit
R
Zhen
Juan
J
Parrington
Ingrid
I
Reith
Maarten E A
ME
Dutta
Aloke K
AK
D000473:Alkanes / Q000737:chemistry* / Q000493:pharmacokinetics; D001596:Benzylamines / Q000737:chemistry* / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D006900:Hydroxylation; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D013329:Structure-Activity Relationship; D027981:Symporters / Q000737:chemistry / Q000378:metabolism*
D000473:Alkanes; D001596:Benzylamines; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D027981:Symporters; C030796:benzylamine; C017573:nonane