Interaction of permanently charged chlorpromazine and dopamine analogs with the striatal D-1 dopaminergic receptor

Although a structural feature common to all dopaminergic agonists and antagonists is a side-chain basic amino group, it is unclear whether this moiety binds to the D-1 dopamine (DA) receptor in the charged or uncharged form. To obtain information on this point, we synthesized permanently charged dimethylsulfonium and quaternary ammonium analogs of chlorpromazine and DA and determined whether these compounds can bind to the D-1 receptor by measuring their abilities to inhibit the binding of SCH 23390, a D-1 receptor antagonist. Chlorpromazine and the dimethylsulfonium and trimethylammonium analogs of chlorpromazine were found to inhibit the binding of [3H]SCH 22390, which was maximally inhibited to the same extent by all three compounds. In addition, inhibition curves for the compounds fit a one-site binding model, indicating binding to a single class of sites. However, while the permanently charged chlorpromazine analogs were able to inhibit [3H]SCH-23390 binding, they were considerably less potent than chlorpromazine. DA and dimethyl DA were also able to inhibit [3H]SCH 23390 binding. However, the permanently charged dimethylsulfonium and trimethylammonium analogs of DA were ineffective in inhibiting [3H]SCH 23390 binding. In addition, the permanently uncharged methylsulfide analog did not inhibit binding. These studies show that permanently charged analogs of chlorpromazine can bind to the striatal D-1 receptor, which is consistent with an anionic recognition site on the D-1 receptor that interacts with antagonists in the cationic form. In addition, it appears that a nitrogen atom is not required for binding to the D-1 receptor, since the sulfonium analog of chlorpromazine bound to the receptor to the same extent as chlorpromazine. However, since the permanently charged or uncharged analogs of DA did not bind to the D-1 receptor, it is still unclear as to whether the charged form of a dopaminergic agonist can bind. The lower potency or ineffectiveness of the permanently charged analogs compared to the parent amines (chlorpromazine, DA, dimethyl DA) in binding to the D-1 receptor may reflect the inability of the permanently charged analogs to undergo hydrogen binding with the anionic site of the receptor.