New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives.
Two series of compounds that are structurally related to benzomorphans, derived by structural modification of arylpiperazines with high 5-HT1A affinity and moderate sigma affinity, were prepared in order to increase sigma affinity and selectivity. All new compounds are N-substituted-omega-(1,2,3,4-tetrahydronaphthalen-1-yl)- or -omega-(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 sigma ([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 sigma affinity (Ki = 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 sigma 2 affinity (Ki = 5.3 nM on [3H]DTG and Ki = 71 nM on [3H]-(+)-pentazocine). Moreover, compound 13, a 1-benzylpiperazine analogue of 14, preserved a dual high 5-HT1A and sigma affinity (Ki = 3.6 nM on [3H]-5-HT and Ki = 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 sigma binding sites, a high 5-HT1A affinity was found for the N-(3-phenylpropyl) derivative 21 (Ki = 4.4 nM) which demonstrated very good selectivity.
Berardi
F
F
Dipartimento Farmaco-chimico, Università di Bari, Italy.
Colabufo
N A
NA
Giudice
G
G
Perrone
R
R
Tortorella
V
V
Govoni
S
S
Lucchi
L
L
D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010423:Pentazocine / Q000494:pharmacology; D010622:Phencyclidine / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011437:Propylamines / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D017478:Receptors, Phencyclidine / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
C097775:1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperazine; C097774:3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3-phenyl-n-propyl)-n-propylamine; D000701:Analgesics, Opioid; C513937:PB28 compound; D010879:Piperazines; D011437:Propylamines; D017448:Receptors, Dopamine D2; D017478:Receptors, Phencyclidine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017480:Receptors, sigma; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; D012701:Serotonin; D010622:Phencyclidine; D010423:Pentazocine