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

Abstract

Our earlier effort to develop constrained analogues of flexible piperidine analogs 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 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 Npropyl side chain with the hydroxyl group attached in the benzylic position was the most potent and selective for DAT (Ki = 8.63 nM; SERT/DAT = 172 and NET/DAT = 48.4).

Synthesis and Biological Evaluation of Bupropion Analogues as Potential Pharmacotherapies for Cocaine Addiction

“…Indirect dopamine agonists − are one class of compounds that have received considerable attention for treatment of cocaine addiction. Studies directed toward the development of indirect dopamine agonists have involved structurally diverse classes of compounds including analogues of 3-phenyltropane, 1,4-dialkylpiperazines (GBR), phenylpiperidine, benztropine, methylphenidate, and mazindol. ,,, …”

Vascular effects of diphenylmethoxypiperidine-derived dopamine uptake inhibitors

“…In these DPP analogs, symmetrical para substituents of the benzene ring were found to be important for high potency in binding to DAT 4 . In addition, several piperidine derivatives have been shown to block an array of dopaminergic, serotoninergic and adrenergic monoamine transporters 5 , reinforcing the physiological relevance of the interactions between the piperidine structure and monoamine transporters.…”

Facile Assembling of Novel 2,3,6,7,9-pentaazabicyclo- [3.3.1]nona-3,7-diene Derivatives under Microwave and Ultrasound Platforms

“…9-Azabicyclo[3.3.1]nonane derivatives possess cytotoxic [10], dopamine D3 receptor ligands [11], high sigma-2 receptor affinities [12], and are used for the treatment of diabetes mellitus [13]. Furthermore, 1,4-diazabicyclo[3.3.1]nonane derivatives are reported to exhibit high in vivo affinity and selectivity for the dopamine transporter (DAT) blockers [14,15]. 3,7-Diazabicyclo[3.3.1]nonanes are reported to be useful in the treatment of cardiac arrhythmias [16], and exhibited anti-platelet, antithrombotic activities [17], as well as high affinities at various nicotinic acetylcholine receptors (nAChRs) [18,19,20].…”

“…Some 1,3,5,7-tetraazabicyclo[3.3.1]nonane derivatives have antithrombotic activities [29]. Although tremendous progress has been achieved in the synthesis of mono-, di-, and tri-azabicyclo[3.3.1]nonanes [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27], the synthesis of tetra- and penta-azabicyclo[3.3.1]nonane frameworks has rarely been disclosed in the literature [30,31,32,33].…”