3-[(Aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives: high-affinity ligands for the serotonin transporter.
The structural requirements for high-affinity binding at the serotonin transporter (SERT) have been investigated through the preparation of some 3-[(aryl)(4-fluorobenzyloxy)methyl]piperidine derivatives. The affinity of synthesised piperidinic compounds (1-4) at the SERT was evaluated by displacement of [3H]-paroxetine binding. Derived inhibition constant (Ki) values were in the same order of magnitude as that of fluoxetine, ranging between 2 and 400 nM. To better define the profiles of these compounds as potential antidepressants, binding affinity for 5-HT1A receptors and alpha2-adrenoceptors was also investigated by competition experiments using [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT) and [3H]rauwolscine as radiolabelled ligands, respectively. Inhibition data indicate that compounds 1-4 possess a very weak affinity for these receptors. The high affinity of compound 1 for SERT indicates that it is worth investigating further.
Nencetti
Susanna
S
Dipartimento di Scienze Farmaceutiche, Facoltà di Farmacia, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy. nencettis@farm.unipi.it
Demontis
Gian Carlo
GC
Mazzoni
Maria Rosa
MR
Betti
Laura
L
Banti
Irene
I
Rossello
Armando
A
Lapucci
Annalina
A
D000818:Animals; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005473:Fluoxetine / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism*; D018341:Receptors, Adrenergic, alpha-2 / Q000378:metabolism; D050486:Serotonin Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship
D000928:Antidepressive Agents; D008024:Ligands; D010880:Piperidines; D018341:Receptors, Adrenergic, alpha-2; D050486:Serotonin Plasma Membrane Transport Proteins; D005473:Fluoxetine; D044282:Receptor, Serotonin, 5-HT1A