New sigma and 5-HT1A receptor ligands: omega-(tetralin-1-yl)-n-alkylamine derivatives

J Med Chem. 1996 Jan 5;39(1):176-82. doi: 10.1021/jm950409c.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / chemical synthesis
  • Analgesics, Opioid / pharmacology
  • Animals
  • Binding Sites / drug effects
  • Brain / drug effects
  • Brain / metabolism
  • Guinea Pigs
  • Magnetic Resonance Spectroscopy
  • Male
  • Pentazocine / pharmacology
  • 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*
  • Serotonin / metabolism
  • Serotonin Receptor Agonists / chemical synthesis
  • Serotonin Receptor Agonists / chemistry
  • Serotonin Receptor Agonists / metabolism*
  • Serotonin Receptor Agonists / pharmacology
  • Structure-Activity Relationship
  • Tetrahydronaphthalenes / chemical synthesis
  • Tetrahydronaphthalenes / chemistry
  • Tetrahydronaphthalenes / metabolism*
  • Tetrahydronaphthalenes / pharmacology

Substances

  • 1-cyclohexyl-4-(3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-n-propyl)piperazine
  • 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)-N-(3-phenyl-n-propyl)-n-propylamine
  • Analgesics, Opioid
  • PB28 compound
  • Piperazines
  • Propylamines
  • Receptors, Dopamine D2
  • Receptors, Phencyclidine
  • Receptors, Serotonin
  • Receptors, Serotonin, 5-HT1
  • Receptors, sigma
  • Serotonin Receptor Agonists
  • Tetrahydronaphthalenes
  • Serotonin
  • Phencyclidine
  • Pentazocine