Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities

B F Thomas, M E Y Francisco, H H Seltzman, J B Thomas, S E Fix, A K Schulz, A F Gilliam, R G Pertwee, L A Stevenson

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

An extended series of alkyl carboxamide analogs of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested for its ability to displace the prototypical cannabinoid ligands ([H-3]CP-55,940, [H-3]2; [H-3]SR141716, [H-3]5; and [H-3]WIN55212-2, [H-3]3), and selected compounds were further characterized by determining their ability to affect guanosine 5'-triphosphate (GTP)-gamma-[S-35] binding and their effects in the mouse vas deferens assay. This systematic evaluation has resulted in the discovery of novel compounds with unique binding properties at the central cannabinoid receptor (CB1) and distinctive pharmacological activities in CB I receptor tissue preparations. Specifically, compounds with nanomolar affinity which are able to fully displace [H-3]5 and [H-3]2, but unable to displace [3 H]3 at similar concentrations, have been synthesized. This selectivity in ligand displacement is unprecedented, in that previously, compounds in every structural class of cannabinoid ligands had always been shown to displace each of these radioligands in a competitive fashion. Furthermore, the selectivity of these compounds appears to impart unique pharmacological properties when tested in a mouse vas deferens assay for CB1 receptor antagonism. (c) 2005 Published by Elsevier Ltd.

Original languageEnglish
Pages (from-to)5463-5474
Number of pages12
JournalBioorganic & Medicinal Chemistry
Volume13
DOIs
Publication statusPublished - 2005

Keywords

  • cannabinoid
  • ligand-receptor
  • binding
  • structure-activity relationships
  • CBI
  • antagonist
  • MOLECULAR-FIELD ANALYSIS
  • SYNAPTIC-TRANSMISSION
  • RAT-BRAIN
  • ANANDAMIDE
  • INHIBITION
  • AGONISTS
  • PHARMACOPHORE
  • REQUIREMENTS
  • CURRENTS
  • LIGANDS

Cite this

Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities. / Thomas, B F ; Francisco, M E Y ; Seltzman, H H ; Thomas, J B ; Fix, S E ; Schulz, A K ; Gilliam, A F ; Pertwee, R G ; Stevenson, L A .

In: Bioorganic & Medicinal Chemistry, Vol. 13, 2005, p. 5463-5474.

Research output: Contribution to journalArticle

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T1 - Synthesis of long-chain amide analogs of the cannabinoid CB1 receptor antagonist N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716) with unique binding selectivities and pharmacological activities

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AU - Francisco, M E Y

AU - Seltzman, H H

AU - Thomas, J B

AU - Fix, S E

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AU - Pertwee, R G

AU - Stevenson, L A

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AB - An extended series of alkyl carboxamide analogs of N-(piperidinyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716; 5) was synthesized. Each compound was tested for its ability to displace the prototypical cannabinoid ligands ([H-3]CP-55,940, [H-3]2; [H-3]SR141716, [H-3]5; and [H-3]WIN55212-2, [H-3]3), and selected compounds were further characterized by determining their ability to affect guanosine 5'-triphosphate (GTP)-gamma-[S-35] binding and their effects in the mouse vas deferens assay. This systematic evaluation has resulted in the discovery of novel compounds with unique binding properties at the central cannabinoid receptor (CB1) and distinctive pharmacological activities in CB I receptor tissue preparations. Specifically, compounds with nanomolar affinity which are able to fully displace [H-3]5 and [H-3]2, but unable to displace [3 H]3 at similar concentrations, have been synthesized. This selectivity in ligand displacement is unprecedented, in that previously, compounds in every structural class of cannabinoid ligands had always been shown to displace each of these radioligands in a competitive fashion. Furthermore, the selectivity of these compounds appears to impart unique pharmacological properties when tested in a mouse vas deferens assay for CB1 receptor antagonism. (c) 2005 Published by Elsevier Ltd.

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KW - SYNAPTIC-TRANSMISSION

KW - RAT-BRAIN

KW - ANANDAMIDE

KW - INHIBITION

KW - AGONISTS

KW - PHARMACOPHORE

KW - REQUIREMENTS

KW - CURRENTS

KW - LIGANDS

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DO - 10.1016/j.bmc.2005.06.005

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EP - 5474

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

SN - 0968-0896

ER -