53915-75-6Relevant academic research and scientific papers
Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites
Choi, Sung-Woon,Elmaleh, David R.,Hanson, Robert N.,Shoup, Timothy M.,Fischman, Alan J.
, p. 4091 - 4102 (2007/10/03)
A series of (bisarylmethoxy)butylpiperidine derivatives was prepared and evaluated in vitro and in vivo to determine the structural requirements necessary for dual activity at the DAT and DA/5-HT receptor sites. These hybrid ligands, constructed by combining pharmacophores specific for the DAT and DA/5-HT receptors, could be useful drugs for treating cocaine addiction by assisting cocaine addicts in maintaining abstinence. The series was evaluated in vitro for DAT and DA/5-HT receptor activity and then selected compounds were tested in vivo for their effects on cocaine-induced hyperlocomotor activity (LMA). The majority of the new compounds demonstrated high to moderate affinity (4-191 nM) for the DAT with 4-hydroxy-4-phenylpiperidine analogues 14 and 15 possessing the greatest affinity. Compounds 15 and 22 exhibited the highest ratio of reuptake inhibition-to-binding (discrimination ratio, DR), 111 and 323, respectively. These derivatives had modest affinity and antagonistic activity for dopamine D2/D3 receptors. Compounds 9 and 15 (DR=0.9 and 111, respectively) stimulated locomotor activity, whereas the other compounds suppressed this response. All compounds tested except for 17 and 21 attenuated cocaine-induced hyperlocomotion.
Design, synthesis, and biological evaluation of novel non-piperazine analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-[bis(4- fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazines as dopamine transporter inhibitors
Choi, Sung-Woon,Elmaleh, David R.,Hanson, Robert N.,Fischman, Alan J.
, p. 3647 - 3656 (2007/10/03)
A series of novel diamine, amine-amide, and piperazinone analogues of N- [2-(bisarylmethoxy)-ethyl]-N'-(phenylpropyl)piperazines, GBR 12909 and 12935, were synthesized and evaluated as inhibitors of presynaptic monoamine neurotransmitter transporters. The primary objective of the study was to determine the structural requirements for selectivity of ligand binding and potency for neurotransmitter reuptake inhibition. In general, the target compounds retained transporter affinity; however, structural variations produced significant effects on reuptake inhibition and transporter selectivity. For example, analogues prepared by replacing the piperazine ring in the GBR structure with an N,N'-dimethylpropyldiamine moiety displayed enhanced selectivity for binding and reuptake inhibition at the norepinephrine (NE) transporter site (e.g. 4 and 5). Congeners in which the amide nitrogen atom was attached to the aralkyl moiety of the GBR molecule showed moderate affinity (K(i) = 51-61 nM) and selectivity for the dopamine transporter (DAT) site. In contrast, introduction of a carbonyl group adjacent to either nitrogen atom of the piperazine ring (e.g. 25 and 27) was not well tolerated. From the compounds prepared, analogue 16 was selected for further evaluation. With this congener, locomotor activity induced by cocaine at a dose of 20 mg/kg was attenuated with an-AD50 (dose attenuating cocaine-induced stimulation by 50%) of 60.0 ± 3.6 mg/kg.
Structure-Activity Studies on Benzhydrol-Containing Nipecotic Acid and Guvacine Derivatives as Potent, Orally-Active Inhibitors of GABA Uptake
Pavia, Michael R.,Lobbestael, Sandra J.,Nugiel, David,Mayhugh, Daniel R.,Gregor, Vlad E.,et al.
, p. 4238 - 4248 (2007/10/02)
The introduction of lipophilic groups onto the ring nitrogen of nipecotic acid and guvacine, two known GABA uptake inhibitors, afforded potent, orally-active anticonvulsant drugs.A series of compounds is reported which explores the structure-activity relationships (SAR) in this series.Among the areas explored: side-chain SAR (aromatic-, heterocyclic-, and tricyclic-containing side chains) and modifications to the tetrahydropyridine ring.The benzhydrol ether-containing side chains afforded the most potent compounds with several exhibiting in vitro IC50 values for GABA uptake of 1 μM (including 5, Table I; 37, 43, Table IV; and 44, Table V).Compound 44 was selected for extensive evaluation and subsequently progressed to Phase 1 clinical trials with severe adverse effects seen after single dose administration to humans.
(Diarylmethoxy alkyl)-1-pyrrolidines and piperidines having cardiovascular activity
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, (2008/06/13)
1-[(diarylmethoxy)alkyl]pyrrolidines and piperidines represented by the following formula: STR1 wherein X is hydrogen or a fluorine atom, Alk is a linear-chain or branched alkyl group having two or three carbon atoms; R 1 and R 2 are hydrogen or a linear-
