One of the most potent drugs in this group is flupenthixol (Fig. 1); a mixture of the cis (a) and tram (P) isomers is a clinically efficaceous antipsychotic agent5 but in dopamine receptor related animal tests the a isomer is much more potent than the 3 form4 (Table 1). In in vitro studies using the dopamine sensitive adenyl cyclase system of the rat corpus striatum as a model of the dopamine receptor, the a isomer is a very potent blocker of the dopamine induced enzyme stimulation whereas the p isomer is almost inactive6 (Table 1). In an attempt to explain how chlorpromazine is able to block dopamine receptors, attention has been focused on a possible spatial complementary relationship between certain portions of the crystal structure of chlorpromazine and dopamine1. Further support for this concept has been obtained from a detailed conformational analysis of 15 drugs of the tricyclic class7. As flupenthixol displays such a marked degree of stereoselectivity in blocking dopamine receptors, it is believed that X-ray analysis of the two isomers could provide additional insight into the various interatomic distance and overall conformational requirements for effective dopamine receptor antagonism. Although the cis and trans geometrical isomers will have differing physical properties this is unlikely to be the sole factor accounting for their differential pharmacological potency, as neuroleptics possessing optically active centres, such as butaclamol, also show a high degree of stereoselectivity7"9. Crystals of each isomer were obtained and the cell dimensions and other related parameters for each compound were found:a-flupenthixol: orthorhombic; Pbca; a = 8.827, b = 20.048, c = 20.251 A; 8 molecules per cell; final R factor 0.066 for 1,094 reflections. p-flupenthixol: monoclinic; P21/c; a = 9.011, b = 15.218, c = 18.493 A; p = 120.37; 4 molecules per cell; current R factor 0.072 for 2,308 reflections.Diffractometer data for both compounds were collected using Cu-Ka radiation to a resolution of 0.89 A (29max of 120) and each structure was solved by the application of locally programmed (G. M. Sheldrick, unpublished) multisolution direct method techniques. Complete details of these structures will be published elsewhere. Figure 1 shows a general view of each isomer based on approximately equivalent orientations of the tricyclic nucleus. The cis or trans configuration at the exocyclic double bond is clearly apparent and each side chain exhibits markedly different conformation although the piperazine rings favour the -CF3 'side' of the molecule in either case. Principal torsion angles for the side chain are shown in Fig. 1. The dihedral angles between the aromatic ring mean planes are 152 and 143 for a and p-flupenthixol respectively. Various lines of evidence support the concept that the preferred conformation of dopamine at its receptor site is the fully extended trans form7; therefore, it has been suggested that the binding site for dopamine's amino group is about 5.1 A from the centre of the aromatic ring7. There is also evidence that the dopamine receptor antagonism by the neuroleptics is competitive1011 and for simplicity this can be considered to indicate occupation, by the neuroleptic, of the same site as the natural agonist. Thus it is of interest to contrast significant intramolecular distances between a and P-flupenthixol. In a-flupenthixol the distances of Nl from the centres of the two aromatic rings A and B (Fig. 1) are 5.82 A and 7.46 A respectively, and the corresponding distances from N2 are much longer, with N2-A = 7.75 A and N2-B = 10.26 A. Fig. 1 a and P isomers of flupenthixol computed from the crystallographic coordinates, together with a chemical representation of the molecules (shown in the a form) on which is indicated labelling referred to in the text. The values of some principal torsion angles (in degrees) for each isomer are shown alongside the bond to which they refer, and where an ambiguity in definition occurs, an arrow marks atoms used in the calculations.Table 1 Comparison of the effects of a and p-flupenthixol on various dopamine receptor systems Antagonism of apomorphineinduced stereotypy in rats ED50(mgkg-1)(ref.4)a-flupenthixol p-flupenthixol 0.3>80 Antagonism of amphetamineinduced stereotypy in rats ED50(mgkg-1)(ref.4)0.07>160 K\ for dopaminesensitive adenyl cyclase antagonism61.0xlO9(M)>5xlO-6(M) This suggests that Nl could bind at the receptor site normally occupied by the amino group of dopamine whereas the aromatic ring A would interact at the site normally influenced by the benzene ring of dopamine. The importance of Nl rather than N2 as the atom involved in the antagonistic binding is supported by comparison with similar distances found in a-chlor-prothixene7'12, a pharmacologically active compound which, however, has only a single N atom in the side chain. There is a marked difference in the almost inactive p-flupenthixol where Nl-A = 6.09 A, Nl-B = 6.46 A, N2-A = 8.24 A and N2-B = 9.30 A, indicating that the a-isomer exhibits a better 'fit' as a dopamine antagonist. Extrapolation from results of crystal structure determinations to the conformation of molecules in physiological conditions has always to be interpreted with caution, but the absence of any unusually close intermolecular contacts in the crystal structures suggests that the observed conformation is not the result of packing forces and that a closely similar conformation could be found in vivo.The A and B rings of the tricyclic nucleus are differentiated by the presence of the-CF3 moiety. This group is of evident importance for pharmacological activity although its mode of action is not clearly understood. It is perhaps of interest to note that the molecular asymmetry introduced in the tricyclic nucleus by the -CF3 group is enhanced in the a form where the difference in the distance of Nl from the centres of the aromatic rings is greater than in the p form7. The X-ray studies reported here were carried out on the free bases. An X-ray analysis of the dihydrochloride salts is in progress to investigate the effect of positive charges on the nitrogen atoms of the piperazine ring on the conformation of these molecules.We thank the MRC for financial support and the SRC for provision of the diffractometer. Olga Kennard is on the External Staff of the MRC. Dr I. Moller-Nielsen of H. Lundbeck and Co., Denmark, provided the specimen crystals.