New σ and 5-HT1A Receptor Ligands:  ω-(Tetralin-1-yl)-n-alkylamine Derivatives

• Published in: Journal of medicinal chemistry Vol. 39; no. 1; pp. 176 - 182
• Main Authors: Berardi, Francesco, Colabufo, Nicola A, Giudice, Giuseppe, Perrone, Roberto, Tortorella, Vincenzo, Govoni, Stefano, Lucchi, Laura
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 05.01.1996; Amer Chemical Soc
• Subjects: Analgesics, Opioid - chemical synthesis; Analgesics, Opioid - pharmacology; Animals; Binding Sites - drug effects; Biological and medical sciences; Brain - drug effects; Brain - metabolism; Chemistry, Medicinal; Guinea Pigs; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pentazocine - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Phencyclidine - metabolism; Piperazines - chemical synthesis; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Propylamines - chemical synthesis; Propylamines - chemistry; Propylamines - metabolism; Propylamines - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2 - metabolism; Receptors, Phencyclidine - metabolism; Receptors, Serotonin - metabolism; Receptors, Serotonin, 5-HT1; Receptors, sigma - metabolism; Science & Technology; Serotonin - metabolism; Serotonin Receptor Agonists - chemical synthesis; Serotonin Receptor Agonists - chemistry; Serotonin Receptor Agonists - metabolism; Serotonin Receptor Agonists - pharmacology; Serotoninergic system; Structure-Activity Relationship; Tetrahydronaphthalenes - chemical synthesis; Tetrahydronaphthalenes - chemistry; Tetrahydronaphthalenes - metabolism; Tetrahydronaphthalenes - pharmacology; PHENCYCLIDINE; AFFINITY; HALOPERIDOL; DRUGS; DOPAMINE; CLASSIFICATION; BINDING-SITES; BRAIN; Rat; Nitrogen heterocycle; Rodentia; Sigma receptor; Central nervous system; Selectivity; In vitro; Naphthalene derivatives; Vertebrata; Biological fixation; Mammalia; Structure activity relation; Animal; Affinity; Piperazine derivatives; Chemical synthesis; Secondary amine; 5-HT1A receptor; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm950409c

Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate σ affinity, were prepared in order to increase σ affinity and selectivity. All new compounds are N-substituted-ω-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -ω-(1,2-dihydronaphthalen-4-yl)-n-alkylamines with, in some cases, a methoxy group on the tetralin moiety. They were tested in radioligand binding assays on σ ([3H]DTG and [3H]-(+)-pentazocine), D-2 dopaminergic, 5-HT1A and 5-HT2 serotonergic, and PCP (phencyclidine) receptors. A first set of compounds bearing a 4-(1-substituted)piperazine moiety as terminal fragment on the alkyl chain showed moderate to high σ affinity (K i = 5.3−139 nM), the most active and selective being 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl]piperazine (14), with probable pronounced σ2 affinity (K i = 5.3 nM on [3H]DTG and K i = 71 nM on [3H]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and σ affinity (K i = 3.6 nM on [3H]-5-HT and K i = 7.0 nM on [3H]DTG). The second set of compounds includes some N-phenylalkyl derivatives of 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propylamine that can be considered to be open-chain derivatives of 4-substituted-1-arylpiperazines. Among these compounds that had a lower activity toward σ binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (K i = 4.4 nM) which demonstrated very good selectivity.