Design, synthesis, and preliminary SAR study of 3- and 6-side-chain-extended tetrahydro-pyran analogues of cis- and trans-(6-benzhydryl-tetrahydropyran-3-yl)-benzylamine.
In our effort to further understand interaction of novel pyran derivatives with monoamine transporters, we have designed, synthesized, and biologically characterized side-chain-extended derivatives of our earlier developed cis- and trans-(6-benzhydryl-tetrahydro-pyran-3-yl)-benzylamine derivatives. Both 3- and 6-position extensions were explored. 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 ability to inhibit binding of [(3)H]WIN 35, 428. The results indicated that extension at the 3-position resulted in loss of activity compared to the original compound I. On the other hand, extension at the 6-position resulted in improvement of activity in the compound cis-12 by 2-fold over the parent compound I indicating favorable interaction. In addition, two glycoside derivatives were designed, synthesized, and biologically characterized. The glycosidic trans-isomer 24 exhibited highest potency for the NET in the current series of compounds.
Department of Pharmaceutical Sciences, Wayne State University, Detroit, MI 48202, USA.
Shijun
S
Zhang
Juan
J
Zhen
Maarten E A
ME
Reith
Aloke K
AK
Dutta
D000818:Animals; D001596:Benzylamines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001667:Binding, Competitive; D003042:Cocaine / Q000031:analogs & derivatives / Q000737:chemistry; D050483:Dopamine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy / Q000379:methods / Q000592:standards; D008958:Models, Molecular; D015394:Molecular Structure; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors; D011714:Pyrans / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012015:Reference Standards; D012680:Sensitivity and Specificity; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001596:Benzylamines; D050483:Dopamine Plasma Membrane Transport Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011714:Pyrans; D050486:Serotonin Plasma Membrane Transport Proteins; C512334:trans-(6-benzhydryl-tetrahydropyran-3-yl)-benzylamine; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; D003042:Cocaine