Novel (4-Phenylpiperidinyl)- and (4-Phenylpiperazinyl)alkyl-Spaced Esters of 1-Phenylcyclopentanecarboxylic Acids as Potent σ-Selective Compounds

Robert L. Hudkins, Richard Mailman, Diane L. DeHaven-Hudkins

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at σ1 and σ2 sites by inhibition of [3H]-(+)-pentazocine (PENT) and [3H]-1,3-di(2-tolyl)guanidine (DTG) binding in guinea pig brain. The phenylpiperidines were more potent σ ligands than the corresponding piperazines. Structural modifications varying the optimal spatial distance between the piperidine nitrogen and ester functions led to the identification of the propyl compound 24 ([3H]PENT Ki = 0.50 nM; [3H]DTG Ki = 1.17 nM) and the butyl derivative 32 ([3H]PENT Ki = 0.51 nM; [3H]DTG Ki = 0.69 nM) as novel high-affinity σ-selective agents. An ethylene spacer was optimum with para-substituted analogs. A notable finding was the discovery of 2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)-cyclopentanecarboxylate hydrochloride (15) (RLH-033), which demonstrated potent affinity for the [3H]PENT-defined σ site with a Ki of 50 pM, selectivity for σ1 over muscarinic M1 (> 17 600-fold), M2 (> 34 200-fold), dopamine D1 (> 58 000-fold), and D2 (> 7000-fold) receptors, and inactivity at phencyclidine, NMDA, and opioid receptors. RLH-033 is a valuable tool which will aid further in understanding the biology of the σ recognition site. Information from this research has further defined the topography of the σ recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.

Original languageEnglish (US)
Pages (from-to)1964-1970
Number of pages7
JournalJournal of Medicinal Chemistry
Volume37
Issue number13
DOIs
StatePublished - Jun 1 1994

Fingerprint

Pentazocine
Esters
Acids
Phencyclidine Receptors
Piperazines
Opioid Receptors
N-Methyl-D-Aspartate Receptors
Cholinergic Agents
Dopamine
Guinea Pigs
Nitrogen
Ligands
Brain
Research
RLH 033

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

@article{f6f8c8b5736a49a09a817b92e0ed18ef,
title = "Novel (4-Phenylpiperidinyl)- and (4-Phenylpiperazinyl)alkyl-Spaced Esters of 1-Phenylcyclopentanecarboxylic Acids as Potent σ-Selective Compounds",
abstract = "A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at σ1 and σ2 sites by inhibition of [3H]-(+)-pentazocine (PENT) and [3H]-1,3-di(2-tolyl)guanidine (DTG) binding in guinea pig brain. The phenylpiperidines were more potent σ ligands than the corresponding piperazines. Structural modifications varying the optimal spatial distance between the piperidine nitrogen and ester functions led to the identification of the propyl compound 24 ([3H]PENT Ki = 0.50 nM; [3H]DTG Ki = 1.17 nM) and the butyl derivative 32 ([3H]PENT Ki = 0.51 nM; [3H]DTG Ki = 0.69 nM) as novel high-affinity σ-selective agents. An ethylene spacer was optimum with para-substituted analogs. A notable finding was the discovery of 2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)-cyclopentanecarboxylate hydrochloride (15) (RLH-033), which demonstrated potent affinity for the [3H]PENT-defined σ site with a Ki of 50 pM, selectivity for σ1 over muscarinic M1 (> 17 600-fold), M2 (> 34 200-fold), dopamine D1 (> 58 000-fold), and D2 (> 7000-fold) receptors, and inactivity at phencyclidine, NMDA, and opioid receptors. RLH-033 is a valuable tool which will aid further in understanding the biology of the σ recognition site. Information from this research has further defined the topography of the σ recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.",
author = "Hudkins, {Robert L.} and Richard Mailman and DeHaven-Hudkins, {Diane L.}",
year = "1994",
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publisher = "American Chemical Society",
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Novel (4-Phenylpiperidinyl)- and (4-Phenylpiperazinyl)alkyl-Spaced Esters of 1-Phenylcyclopentanecarboxylic Acids as Potent σ-Selective Compounds. / Hudkins, Robert L.; Mailman, Richard; DeHaven-Hudkins, Diane L.

In: Journal of Medicinal Chemistry, Vol. 37, No. 13, 01.06.1994, p. 1964-1970.

Research output: Contribution to journalArticle

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AB - A series of novel 4-phenylpiperidinyl and (4-phenylpiperazinyl)alkyl 1-phenylcyclopentanecarboxylates was synthesized and evaluated for affinity at σ1 and σ2 sites by inhibition of [3H]-(+)-pentazocine (PENT) and [3H]-1,3-di(2-tolyl)guanidine (DTG) binding in guinea pig brain. The phenylpiperidines were more potent σ ligands than the corresponding piperazines. Structural modifications varying the optimal spatial distance between the piperidine nitrogen and ester functions led to the identification of the propyl compound 24 ([3H]PENT Ki = 0.50 nM; [3H]DTG Ki = 1.17 nM) and the butyl derivative 32 ([3H]PENT Ki = 0.51 nM; [3H]DTG Ki = 0.69 nM) as novel high-affinity σ-selective agents. An ethylene spacer was optimum with para-substituted analogs. A notable finding was the discovery of 2-(4-phenylpiperidinyl)ethyl 1-(4-nitrophenyl)-cyclopentanecarboxylate hydrochloride (15) (RLH-033), which demonstrated potent affinity for the [3H]PENT-defined σ site with a Ki of 50 pM, selectivity for σ1 over muscarinic M1 (> 17 600-fold), M2 (> 34 200-fold), dopamine D1 (> 58 000-fold), and D2 (> 7000-fold) receptors, and inactivity at phencyclidine, NMDA, and opioid receptors. RLH-033 is a valuable tool which will aid further in understanding the biology of the σ recognition site. Information from this research has further defined the topography of the σ recognition site, which may provide an explanation for the diverse structures which bind with relatively high affinity.

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