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

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).

Tranylcypromine Substituted cis-Hydroxycyclobutylnaphthamides as Potent and Selective Dopamine D3 Receptor Antagonists

“…These are lower than the selectivities observed for these compounds for the rat D 3 receptor over the rat D 2 receptor. The known D 3 antagonists N -methylspiperone, 26 eticlopride, 27 raclopride, 28 and butaclamol, 29 all bind to the human D 3 receptor with high affinities but show no selectivity between the human D 2 and D 3 receptors (Table 2). In comparison, PG619 22 and PG648, 12 two previously reported selective D 3 antagonists, bind to the human D 3 receptor with K i values of 6.70 and 1.88 nM, respectively, displaying selectivities of 163- and 397-fold respectively, for the human D 3 receptor over the human D 2 receptor.…”

A mechanistic study on the disproportionation and oxidative degradation of phenothiazine derivatives by manganese(III) complexes in phosphate acidic media

“…In other cases, k obs values are similar to each other. Due to the fact that the increase in the value of the observed rate constant with increasing pH for both trifluoperazine and chlorpromazine is similar and covers the pH range outside the pK a of these compounds (9.2 for chlorpromazine) [35], changes might be attributed to either changes in the coordination sphere of the complex of manganese(III) or a change in rate of disproportionation. At pH [ 2, manganese(III) undergoes a further coordination reaction with pyrophosphates; this process causes the blue-shift of the transition band from 513 to 479 nm (pH = 5.5).…”

Butaclamol: Absolute configuration, crystal and molecular conformation

“…In a recent reevaluation of this, the compound was found to have a pKa of 7.2 and it was concluded that this was about 1 pKa unit below expectations based on structurally related compounds (Chrzanowski et al, 1985). This implies that either the unprotonated form of the molecule is stabilized in some way or that the protonated form is destabilized.…”