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Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor

David A Perrey1, Nadezhda A German, Brian P Gilmour

  • 1Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.

Journal of Medicinal Chemistry
|August 15, 2013
PubMed

Insights

Selective OX1 receptor antagonists may treat drug addiction. Researchers developed novel tetrahydroisoquinoline compounds, with Compound 72 showing promise by reducing cocaine-induced place preference in rats, indicating therapeutic potential.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Medicinal Chemistry

Background:

  • The orexin 1 (OX1) receptor is increasingly implicated in reward pathways.
  • OX1 receptor antagonism presents a potential therapeutic strategy for substance use disorders.

Purpose of the Study:

  • To design and synthesize novel OX1 selective antagonists.
  • To investigate the structure-activity relationships (SAR) of tetrahydroisoquinoline derivatives for OX1 antagonism.
  • To evaluate the efficacy of a lead compound in a preclinical model of drug addiction.

Main Methods:

  • Synthesis of substituted tetrahydroisoquinoline compounds.
  • In vitro evaluation using OX1 and OX2 calcium mobilization assays.
  • Structure-activity relationship (SAR) analysis and computational modeling.
  • In vivo assessment of cocaine-induced place preference in a rat model.

Main Results:

  • SAR studies identified key structural requirements for OX1 receptor antagonism, including limited steric tolerance and electron deficiency at the 7-position.
  • Pyridylmethyl groups at the acetamide position were optimal for activity.
  • A pharmacophore model was developed, consistent with SAR findings.
  • Compound 72 demonstrated significant attenuation of cocaine-induced place preference in rats.

Conclusions:

  • Novel tetrahydroisoquinoline derivatives were successfully designed and synthesized as selective OX1 antagonists.
  • Compound 72 exhibits preclinical efficacy in a cocaine addiction model.
  • These findings support the development of OX1 antagonists as a potential treatment for drug addiction.

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