title: New N-n-propyl-substituted 3-aryl- and 3-cyclohexylpiperidines as partial agonists at the D4 dopamine receptor.
abstract: We have previously reported that compounds dimethyl-substituted on the phenyl ring of N-n-propyl-3-phenylpiperidines (PPEs) have a high (nM) affinity and selectivity toward the D(4) dopamine receptor (D(4) DAR) with m,p-dimethyl PPE (1) having the highest affinity and selectivity. In the present paper we have investigated the role of the methyl substitution by the synthesis of monomethylated (2a-c) and nonmethylated (2d) PPEs followed by the characterization of their biological properties using receptor binding assays. Our findings reveal that the methyl substitution of the phenyl ring is not necessary for a high and selective binding affinity to the D(4) DAR. Moreover, we have also synthesized cyclohexylpiperidines (CHPEs, 3a-d), which all showed higher binding affinities for the D(4) DAR than their aromatic counterparts. These results indicate that a pi-pi type interaction of the phenyl ring of PPEs with the D(4) DAR might not be essential, whereas a simple hydrophobic attraction between the cyclohexyl substituent of CHPEs and a hypothesized lipophilic pocket of the receptor might be crucial. Furthermore, functional assays indicate that 3d, as well as 1, are partial agonist at the D(4) DAR and therefore might represent new pharmacological tools to investigate the role of D(4) DAR activation in the control of cognitive functions and emotional states in health and disease.
authors.affiliation: Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Macchia
authors.forename: Luigi
authors.initials: L
authors.lastname: Cervetto
authors.forename: Gian Carlo
authors.initials: GC
authors.lastname: Demontis
authors.forename: Biancamaria
authors.initials: B
authors.lastname: Longoni
authors.forename: Filippo
authors.initials: F
authors.lastname: Minutolo
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Orlandini
authors.forename: Gabriella
authors.initials: G
authors.lastname: Ortore
authors.forename: Chiara
authors.initials: C
authors.lastname: Papi
authors.forename: Andrea
authors.initials: A
authors.lastname: Sbrana
authors.forename: Bruno
authors.initials: B
authors.lastname: Macchia
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism; D018360:Crystallography, X-Ray; D018491:Dopamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008550:Melatonin / Q000096:biosynthesis; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011684:Purine Nucleosides; D011744:Pyrimidinones / Q000737:chemistry; D011758:Pyrroles / Q000737:chemistry; D011869:Radioligand Assay; D017448:Receptors, Dopamine D2 / Q000187:drug effects* / Q000378:metabolism; D050638:Receptors, Dopamine D4; D012160:Retina / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D018491:Dopamine Agonists; D006150:Guanine Nucleotides; D010880:Piperidines; D011684:Purine Nucleosides; D011744:Pyrimidinones; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050638:Receptors, Dopamine D4; C113101:forodesine; D008550:Melatonin