Pharmacological Characterization of SIB-1765F: A Novel Cholinergic Ion Channel Agonist

  1. Aida I. Sacaan,
  2. Richard T. Reid,
  3. Emily M. Santori,
  4. Pamala Adams,
  5. Lucia D. Correa,
  6. Lorrence S. Mahaffy,
  7. Leo Bleicher,
  8. Nicholas D. P. Cosford,
  9. Kenneth A. Stauderman,
  10. Ian A. McDonald,
  11. Tadimeti S. Rao and
  12. G. Kenneth Lloyd
  1. SIBIA Neurosciences, Inc., La Jolla, California

    Abstract

    Nicotine, the prototypical agonist for neuronal nicotinic acetylcholine receptors (NAChR), nonselectively activates NAChR limiting its use in elucidating the function of NAChR subtypes. SIB-1765F is a subtype selective NAChR agonist that displaces [3H]-nicotine binding with an IC50 of 4.6 nM and [3H]-cytisine binding with an IC50 of 12.2 nM which is 2000- to 6000-fold lower than its displacement of [3H]-QNB or [125I]-α-bungarotoxin. SIB-1765F did not inhibit human or rat cholinesterases or the uptake of [3H]-DA in synaptosomal preparations. SIB-1765F mimicked (−)-nicotine in stimulating [3H]-DA release from rat striatal and olfactory tubercle slices, with EC50 values of 99.6 and 39.6 μM, respectively. Such stimulation was sensitive to mecamylamine and DHβE. SIB-1765F also released endogenous DA in the striatum and the nucleus accumbens as measured by in vivomicrodialysis. SIB-1765F was less efficacious than (−)-nicotine at stimulating [3H]-NE release from rat hippocampal slices; in contrast, SIB-1765F increased [3H]-NE release from rat thalamic and cortical slices with efficacies approaching those of (−)-nicotine. Similar to (−)-nicotine and (±)-epibatidine, subcutaneous administration of SIB-1765F increased the turnover rate of dopamine ex vivo both in the striatum and olfactory tubercles in a mecamylamine-sensitive manner. Because the release of striatal DA and hippocampal NE appears to be regulated by distinct NAChR, differential effects of SIB-1765F on striatal DA and hippocampal NE release supports the NAChR subtype selectivity of SIB-1765F compared to (−)-nicotine. This is further demonstrated by observations showing that SIB-1765F has a higher affinity for hα4β2 NAChR relative to hα4β4 NAChRs in displacing [3H]-epibatidine binding and increasing cytosolic Ca++ concentration in cell lines stably expressing hα4β2 or hα4β4.

    Footnotes

    • Send reprint requests to: Dr. Aida I. Sacaan, SIBIA Neurosciences, Inc., 505 Coast Boulevard South, Suite 300, La Jolla, CA 92037-4641.

    • Abbreviations:
      DA
      dopamine
      NE
      norepinephrine
      d-TC
      d-tubocurarine
      DHβE
      dihydro β-erythroidine
      Mec
      mecamylamine
      α-BTX
      α-bungarotoxin
      NAChR
      neuronal nicotinic acetylcholine receptors
      DTG
      1,3-di(2-tolyl) guanidine
      DOPAC
      dihydroxyphenylacetic acid
      HVA
      homovanillic acid
      QNB
      quinuclidinyl benzilate
      MAChR
      muscarinic acetylcholine receptor
      PD
      Parkinson’s disease
      AD
      Alzheimer disease
      HBS
      HEPES buffered saline
      PFC
      prefrontal cortex
      HPLC
      high performance liquid chromatography
      DMSO
      dimethyl sulfoxide
      BTC
      butyrylthiocholine
      • Received April 26, 1996.
      • Accepted August 8, 1996.
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    1. JPET January 1, 1997 vol. 280 no. 1 373-383
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