Novel (bisarylmethoxy)butylpiperidine analogues as neurotransmitter transporter inhibitors with activity at dopamine receptor sites.
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 D(2)/D(3) 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.
Choi
Sung-Woon
SW
Division of Nuclear Medicine, Department of Radiology, Massachusetts General Hospital, Boston 02114, USA.
Elmaleh
David R
DR
Hanson
Robert N
RN
Shoup
Timothy M
TM
Fischman
Alan J
AJ
D000818:Animals; D002460:Cell Line; D003042:Cocaine / Q000008:administration & dosage / Q000494:pharmacology; D019970:Cocaine-Related Disorders / Q000188:drug therapy / Q000517:prevention & control; D018492:Dopamine Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D008024:Ligands; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins / Q000737:chemistry; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D011954:Receptors, Dopamine / Q000737:chemistry*; D011985:Receptors, Serotonin / Q000737:chemistry; D013329:Structure-Activity Relationship
D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D010880:Piperidines; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; C493214:SLC6A3 protein, human; C493215:Slc6a3 protein, mouse; C493216:Slc6a3 protein, rat; D003042:Cocaine