Mapping the dopamine receptor. 1. Features derived from modifications in ring E of the neuroleptic butaclamol.

Several analogues of the neuroleptic agent butaclamol, having modifications in the ring E region of the molecule, have been synthesized. Pharmacological evaluation identified two of the analogues as being equipotent to butaclamol, namely, anhydrobutaclamol (8) and deoxybutaclamol (9a). The molecular structures of both the active and inactive analogues were analyzed and the results have been used for mapping the central dopamine receptor. The existence of a previously proposed lipophilic accessory binding site on the receptor macromolecule has been confirmed. Its minimum dimensions, as well as its locus with respect to the primary binding sites, have been defined. A receptor model incorporating the above features is proposed.

Mapping the dopamine receptor. 2. Features derived from modifications in the rings A/B region of the neuroleptic butaclamol.

Several analogues of the neuroleptic agent butaclamol having modifications in the rings A/B region of the molecule have been synthesized. Pharmacological evaluation identified the benzo[5,6]cyclohepta analogue 2b, isobutaclamol, as being equipotent to butaclamol. The molecular structure of this compound has been analyzed, and the results have been used for mapping the central dopamine receptor. A planar catechol primary binding site, composed of alpha and beta regions, has been identified and its minimal dimensions deduced. Its locus with respect to the nitrogen location site and its complementary hydrogen bond donor site has been specified. Using a Cartesian coordinate system, a receptor model is proposed which incorporates the above-mentioned features. The receptor model has been used to rationalize the observed chirality of the central dopamine receptor.

Use of the butaclamol template in a search for antipsychotic agents with lessened side effects.

A number of molecular similarities between the antipsychotic agents butaclamol and clozapine were noted. Based on the premise that this was a strong indicator of a common mechanism of action (i.e., binding at the antagonist state of the dopamine receptor), a research approach was described. Three simplified analogues (4,8, and 12a) of butaclamol which still retained the molecular functionalities of the parent structure were synthesized and tested in the haloperidol receptor assay. 1-(5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene)-4-tert-butyl-4-piperidine (12a) displaced tritiated haloperidol with an IC50 value of 2.4 nM, as compared to a value of 0.5 nM for butaclamol However, when 12a was tested in vivo or in the spiroperidol receptor assay it was found to be considerably less potent.

Neuroleptics related to butaclamol. An investigation of the effects of chlorine substituents on the aromatic rings.

The synthesis of analogues of the antipsychotic drug butaclamol bearing chloro substituents on the benzene rings is described. On the basis of a perceived topographical similarity of a putative chlorophenylethylamine pharmacophore present in these analogues and in VUFB-10032 and doclothepin, agents related to octoclothepin which do not induce catalepsy, they have been tested for "noncataleptic" neuroleptic activity. None of the butaclamol analogues exhibit this type of activity. Depending on the position of the chlorine, the analogues either retained butaclamol-like activity or were inactive.

Neuroleptics related to butaclamol. Synthesis and some psychopharmacological effects of a series of 3-aryl analogues.

The synthesis and some pharmacological effects of 16 3-aryl analogues of butaclamol, a new antipsychotic drug, are described. The animal models were predictive of neuroleptic activity as well as side effects commonly associated with neuroleptic therapy. The results indicate that the 3-substituent plays a critical role with regard to the potency of the compounds as well as to their tendencies to induce extrapyramidal side effects and/or hypotension.