Piquindone

Tourette's disorder is a neuropsychiatric disorder characterised clinically by motor and vocal tics, which may be associated to conductual disorders such as obsessive-compulsive disorder (OCD) and attention-deficit hyperactivity disorder (ADHD). Although the neurochemistry of Tourette's disorder is not well known, there are some effective therapies for tics, OCD and ADHD. However, these are not devoid of adverse effects. Tics only require treatment when they interfere with the functioning of the patient. If therapy is needed, monotherapy at the minimal effective dose is desirable, but some patients may require two or more drugs. The most frequently used drugs for tics are antipsychotics (mainly pimozide and haloperidol) and clonidine. The potential usefulness of atypical antipsychotic drugs (risperidone, olanzapine, clozapine, ziprasidone) and other dopaminergic drugs (fluphenazine, sulpiride, tiapride, metoclopramide, piquindone, tetrabenazine), clonazepam, calcium channel antagonists, botulinum toxin, dopamine agonists, selegiline, and other drugs is discussed. The drugs of choice for OCD in patients with Tourette's disorder are the selective serotonin reuptake inhibitors (SSRIs), although the tricyclic antidepressant clomiplamine, which inhibits both serotonin and noradrenaline uptake, has also been found to be useful. ADHD can be treated with some psychostimulants, mainly methylphenidate, although these drugs must be used with caution. Other potentially useful drugs for the treatment of ADHD in patients with Tourette's disorder are clonidine, guanfacine, selegiline, some tricyclic antidepressants, sertraline, pimozide and clonazepam. Finally, the potential value of some nonpharmacological therapies (hypnotherapy, biofeedback, conductual therapies, electroconvulsive therapy, acupuncture and surgery) is briefly reviewed.

This study is an attempt to incorporate the butyrophenones, an important class of nontricyclic antipsychotic drugs, into a previously proposed pharmacophore model of tricyclic dopamine D2 receptor antagonist ligands. Conformational energy calculations were performed using the MM3-92 program on spiperone, as a representative butyrophenone, and milenperone and R48455, as related compounds with more limited conformational freedom. Twenty seven conformers were evaluated for spiperone with MM3-92 calculations and nine of these were within 1.1 kcal/mole of the global minima indicating the flexibility of the compound. A conformational analysis of twenty crystal structures of butyrophenones was also performed and six distinct conformers were represented. All of the energy minimized conformers of spiperone were superimposed in a least squares sense onto loxapine as a relatively rigid, typical D2 antagonist and a pair of mirror image conformers, which are observed in one crystal structure of spiperone, were found to be the best fit. However, it was not possible to discriminate between these two conformers since they fit the pharmacophore model equally well. The para-fluoro and carbonyl group of the butyrophenones were found to correspond best to the oxygen and chlorine atoms of loxapine, respectively. The conformations of milenperone and R48455 were also consistent with the two putative biologically active forms of spiperone and the pharmacophore model. Conformational energy calculations were also performed on molindone, an antipsychotic drug in clinical use, which can be related to the butyrophenones since both have a carbonyl group adjacent to an aromatic ring. A putative biologically active form was proposed for molindone and this was related to the structure of piquindone, a rigid analog of molindone. All of the compounds were found to be entirely consistent with the pharmacophore model. However, as previously found, there is great variability in the distance between the ammonium nitrogen and the center of the relevant aromatic ring with the most extreme case in the present study being R48455 where the distance is 7.2 A. The results of the present study should also be relevant to the structures of novel, atypical antipsychotic drugs such as risperidone which appear to be analogs of the butyrophenones.