title: Novel potent sigma 1 ligands: N-[omega-(tetralin-1-yl)alkyl]piperidine derivatives.
abstract: A series of substituted N-[(tetralin-1-yl)alkyl]piperidines and a number of related N-di-n-propyl-[(tetralin-1-yl)alkyl]amines were prepared. Structural modifications such as piperidine substitutions, intermediate chain lengthening, and the nature of the aromatic ring were explored in order to identify structural requirements for selective sigma 1 affinity. They were tested in radioligand binding assays on sigma 1, 5-HT1A and 5-HT2 serotonergic, PCP (phencyclidine), and D-2 dopaminergic receptors. Almost all the compounds reported here showed a high to superpotent sigma 1 affinity, and some compounds also demonstrated a widespread selectivity over the other receptors. In [3H]-(+)-pentazocine binding, 3,3-dimethyl-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n- propyl] piperidine (24) and 3,3-dimethyl-1-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)-n- butyl]piperidine (26) reached the lowest Ki values (0.4 and 0.8 nM, respectively); compound 24 also demonstrated a considerable PCP affinity (Ki = 34.2 nM), whereas compound 26 was suitably selective. Furthermore the presence of a 4-benzyl substituent on the piperidine ring (compound 16, Ki = 3.9 nM on sigma 1 sites) caused an increase in 5-HT1A affinity (Ki < 0.14 nM).
authors.affiliation: Dipartimento Farmaco-chimico, Università di Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Berardi
authors.forename: G
authors.initials: G
authors.lastname: Giudice
authors.forename: R
authors.initials: R
authors.lastname: Perrone
authors.forename: V
authors.initials: V
authors.lastname: Tortorella
authors.forename: S
authors.initials: S
authors.lastname: Govoni
authors.forename: L
authors.initials: L
authors.lastname: Lucchi
mesh_terms: D000818:Animals; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007650:Ketanserin / Q000378:metabolism; D010622:Phencyclidine / Q000378:metabolism; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D017478:Receptors, Phencyclidine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma / Q000378:metabolism*; D013134:Spiperone / Q000378:metabolism; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D010880:Piperidines; D017478:Receptors, Phencyclidine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes; D013134:Spiperone; D007650:Ketanserin; D010622:Phencyclidine