Dopamine receptor topography. Characterization of antagonist requirements of striatal dopamine-sensitive adenylate cyclase using protoberberine alkaloids

Representative protoberberine-related alkaloids, i.e. tetrahydroprotoberberines (THPB), quaternary protoberberine salts (Quat. PB) and quaternary dehydroprotoberberine salts (Dehyd. Quat. PB), have been used to characterize the geometric and stereospecific requirements of antagonists of the dopamine receptor. The optical isomers of 2, 3, 10, 11-THPB were tested for their ability to antagonize dopamine stimulated adenylate cyclase activity. The results indicate that (±)-2. 3, 10, 11-THPB inhibited the ability of 100 μM dopamine to elevate adenylate cyclase in homogenates of the rat caudate nucleus. The ic₅₀ was observed to be 6 μM. The S-(?)-isomer of 2, 3, 10, 11-THPB was a more potent antagonist of dopaminesensitive adenylate cyclase activity than the R-(+)-isomer. The ic₅₀ for (?)-THPB was 1μM whereas that for the (+)-isomer was 50 μM. The data also show that the positional isomer, 2, 3, 9, 10-THPB, antagonized dopamine activation of adenylate cyclase with the same degree of potency as 2, 3, 10, 11-THPB. Exhaustive O-methylation of THPB at all four hydroxyl positions, the 2, 3-position of the “a” ring and the 10, 11-position of the “d” ring as in xylopinine or the 2, 3-position of the “a” ring and the 9, 10-position of the “d” ring as in tetrahydropalmatine, rendered these compounds weak antagonists of the dopamine response. Selective O-methylation of the THPB molecule markedly altered the potency of the resultant compounds as antagonists depending on the position of the O-methyl substitution. Overall, these data are consistent with the idea that the orientation of the nitrogen atom in a fixed (cis: gauche) position 2 carbon atoms from a catechol nucleus renders antagonist properties to these compounds which interact with the dopamine receptor.