The pKa of butaclamol and the mode of butaclamol binding to central dopamine receptors

Authors:
  • FCFrank A. Chrzanowski
    Frank A. Chrzanowski
  • BMBeth A. McGrogan
    Beth A. McGrogan
  • BMBruce E. Maryanoff
    Bruce E. Maryanoff
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Abstract
The pKa values for butaclamol (1), 1,2,3,5,6,10b beta-hexahydro-6 alpha-phenylpyrrolo[2,1-alpha]isoquinoline (2, McN-4612-Y), and 2-tert-butyl-1,3,4,6,7,11b beta-hexahydro-7 beta-phenyl-2H-benzo[alpha]quinolizin-2 alpha-ol (3, McN-4171) were determined to be 7.2, 9.1, and 7.0, respectively. The values for 1 and 3 are anomalous; however, the value for 1 (7.2) is not as low as the one reported in the literature (pKa = 5.9). We also determined pKa values for apomorphine, chlorpromazine, and lidocaine, for reference purposes (7.6, 9.2, and 7.9, respectively). The results indicate that 1 would not be predominantly unprotonated under the physiological conditions of receptor binding, rather it would be about 50% protonated. This fact may contravene a suggested binding model used to map the central dopamine receptor (viz., ref 3).