2-Phenylpyrroles were synthesized as conformationally restricted analogues of the substituted benzamide sultopride and the butyrophenones haloperidol and fluanisone. Dopamine antagonistic activity is maintained if the 2-phenylpyrrole side chain is linked to the pharmacophoric N-ethylpyrrolidine moiety of sultopride or to the 4-substituted piperazine moiety of fluanisone but is lost if the 2-phenylpyrrole is combined with the 4-substituted piperidine moiety of haloperidol. The 2-phenylpyrrole analogue 1 of sultopride is in vitro 0.25 and in vivo 3 times as potent as the parent compound. Its binding to the dopamine D-2 receptors is, in analogy to the substituted benzamides, strongly sodium-dependent. The 2-(4-fluorophenyl)pyrrole analogue 5 of fluanisone is superior in vitro as well as in vivo to the corresponding benzamide 7 and the butyrophenone fluanisone. The increase in activity is not only due to a higher affinity for the D-2 receptors but also to an enhanced oral absorption (ratio po/ip = 4.5 vs 40 for the benzamide and 60 for fluanisone). Compound 5 is further characterized by a high selectivity for the D-2 receptors, in contrast to the benzamide and butyrophenone analogues (ratio D-2/alpha 1 = 60, 2.0, and 0.3, respectively). The binding to the D-2 receptors has little dependence on sodium. The 2-phenylpyrrole 5 shares with the benzamide 7 a low potential to induce catalepsy, which is in contrast to haloperidol. So, 5-(4-fluorophenyl)-2-[[4-(2-methoxyphenyl)-1-piperazinyl]methyl]pyrrole (5) is the prototype of a new class of sodium-independent dopamine D-2 antagonists, which may be particularly useful as potential antipsychotics with a low propensity to induce acute extrapyramidal side effects.