Discovery of novel trisubstituted asymmetric derivatives of (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol, exhibiting high affinity for serotonin and norepinephrine transporters in a stereospecific manner.
In our structure-activity relationship study on 3,6-disubstituted pyran derivatives, we have carried out asymmetric synthesis and biological characterization of trisubstituted (2S,4R,5R)-2-benzhydryl-5-benzylaminotetrahydropyran-4-ol and (3S,4R,6S)-6-benzhydryl-4-benzylaminotetrahydropyran-3-ol derivatives and their enantiomers. All synthesized derivatives were tested for their affinities for the dopamine transporter (DAT), serotonin 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 affinity at the DAT by their inhibition of [(3)H]WIN 35,428. Biological results indicated that regioselectivity and stereoselectivity played important roles in determining activity for monoamine transporters as only (-)-isomers of 2-benzhydryl-5-benzylaminotetrahydropyran-4-ol derivatives exhibited appreciable potency for the monoamine transporters, in particular for the SERT and NET. Among the active analogues, (-)-9d exhibited potent and selective affinity at the NET (K(i), [(3)H]NE = 4.92 nM; DAT/NET = 91 and SERT/NET = 140). One of the derivatives with p-methoxybenzyl substitution, (-)-9a, was potent at both SERT and NET (K(i), [(3)H]-5-HT = 25.9 and [(3)H]NE = 15.8 nM, respectively). In the active analogue series ((-)-9a-(-)-9e), a cis-relationship between the biphenyl and the amino moiety was maintained for the SERT and NET interactions, as was observed with our earlier 3,6-disubstituted pyran compounds for the DAT interaction. To the best of our knowledge, this current series of compounds represents a novel class of pyran derivatives as blockers for monoamine transporters.
Zhang
Shijun
S
Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, USA.
Zhen
Juan
J
Reith
Maarten E A
ME
Dutta
Aloke K
AK
D000818:Animals; D001559:Benzhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050486:Serotonin Plasma Membrane Transport Proteins; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D027981:Symporters / Q000378:metabolism*
D001559:Benzhydryl Compounds; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans; D050486:Serotonin Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; C493216:Slc6a3 protein, rat; C493232:Slc6a4 protein, rat; D027981:Symporters