Antipsychotic Properties of the Partial Dopamine Agonist (−)-3-(3-Hydroxyphenyl)-N-n-Propylpiperidine (Preclamol) in Schizophrenia

Abstract

Background: In an ongoing effort to characterize the clinical pharmacologic profile of the partial dopamine agonist (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(−)-3PPP], we administered it to drug-free schizophrenic patients in two consecutive studies.

Methods: In a preliminary dose-finding study, 9 patients were treated using a 6-week placebo-controlled crossover design. Then, to properly demonstrate the antipsychotic effect, we carried out an early efficacy study; here 10 patients received (−)-3PPP, 300 mg B.I.D., in a 1-week placebo-controlled crossover study.

Results: Dose-Finding Study: (−)-3PPP showed apparent antipsychotic effect in repeated dosing, with 300 mg B.I.D. being the most effective dose for antipsychotic action; however, the apparent antipsychotic action was not sustained for longer than 1 week, presumably because of desensitization of the receptor by the agonist.

Early Efficacy Study: Positive symptoms as measured by the Psychosis Change Scale decreased in 1 week by 30% with (−)-3PPP compared to placebo, and negative symptoms measured with the Brief Psychiatric Rating Scale Withdrawal subscale decreased by 28% with the drug. In both studies, (−)-3PPP lacked any evidence of motor side effects.

Conclusions: These data show that psychotic symptoms decrease with (−)-3PPP and suggest that the treatment of schizophrenia with partial dopamine agonist is a promising strategy. Future attention will be directed toward testing techniques to diminish the tachyphylaxis to allow an ongoing therapeutic effect.

Introduction

In laboratory experiments, dopamine agonists have been shown to reduce the synthesis and release of dopamine from dopamine-containing midbrain neurons in experimental animals, presumably through an agonist action at the dopamine autoreceptor (Kehr et al 1972; Bunney et al 1973; Walters and Roth 1975; Walters et al 1975). Moreover, at low doses, dopamine agonists appear to preferentially stimulate the autoreceptor because of the higher sensitivity of this receptor for dopamine and its agonists (Carlsson 1975; Roth 1979). This results in a paradoxical antidopaminergic action of dopamine agonists (Walters and Roth 1976; Skirboll et al 1979). This preclinical action serves as the theoretical basis for evaluating the antipsychotic action of dopamine agonists in schizophrenia, despite the known therapeutic action of dopamine D₂ receptor antagonists in psychosis (Delay and Deniker 1952; Klein and Davis 1969). Based on this preclinical rationale, apomorphine was first tested in schizophrenia (Smith et al 1977; Tamminga et al 1978; Corsini et al 1977, Corsini et al 1981; Jeste et al 1983) as was N-propylnorapomorphine (Tamminga et al 1986), and demonstrated to have an antipsychotic effect. Although these agonist treatments showed antipsychotic activity, several other agonist studies, in different designs usually involving chronic treatment, failed to confirm a dopamine agonist-induced antipsychotic effect (Tamminga and Schaffer 1979; Angrist et al 1980; Ferrier et al 1984; Levy et al 1984). These conflicting findings signaled the need to reexamine this strategy. Meanwhile, partial dopamine agonists with their reduced intrinsic activity and even higher preferential affinity for the autoreceptor were synthesized, seemingly even better designed to test this hypothesis. Because the partial dopamine agonist (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine [(−)-3PPP; Preclamol] was already extensively characterized preclinically, we selected this compound to test for efficacy in schizophrenic persons with florid psychosis.

3PPP is a phenylpiperidine derivative and a dopamine congener. It exists as a racemic mixture with each enantiomer showing different, sometimes opposite, effects at the dopamine synapse (Hjorth et al 1983). The negative enantiomer (−)-3PPP preferentially stimulates the dopamine autoreceptor, but can function as an agonist at the postsynaptic site as well. (−)-3PPP has little significant affinity for other monoaminergic, or other receptors (Clark et al 1985a), including the D₁, serotonin 5-HT_1A, and 5-HT₂ (R. Lahti, unpublished data); however, its actions appear to be at least partially selective for limbic regions. It reduces open field exploratory behavior in rats following injection into nucleus accumbens, but not into striatum (Svensson and Ahlenius 1983). It reduces locomotor activity in mice, but even at high doses fails to induce catalepsy (Arnt 1983; Hjorth et al 1983). It only partially and never fully reverses the increase in dopamine synthesis produced by gammabutyrolactone (GBL), presumably by its full occupation but only partial agonist activity at the dopamine (DA) autoreceptor (Clark et al 1985a, Clark et al 1985b; Pugsley et al 1995). (−)-3PPP only partially inhibits the firing of DA cells in the central nervous system and this action is fully reversed by haloperidol (Clark et al 1985a; Meltzer et al 1995). With the developing concept of partial receptor agonists (Ariens 1983; Kenakin 1993), (−)-3PPP became the first partial dopamine agonist widely evaluated pharmacologically for its effects on dopamine system function (Bergstrom et al 1986). Based on the receptor state binding affinity ratio method or the inhibition of cyclic adenosine monophosphate (AMP) to determine intrinsic activity, (−)-3PPP has an intrinsic activity at the D₂ receptor of 35%, at the D₃ receptor of 44%, and at the D₄ receptor of 83% (Lahti et al 1992, Lahti et al 1996; Chio et al 1994). In Phase I human safety studies carried out in schizophrenic individuals, the use of (−)-3PPP has been shown to be safe, its single dose kinetics defined, and the presence of efficacy suggested (Tamminga et al 1992).

We report here the results of two sequential double-blind, placebo-controlled studies of (−)-3PPP in neuroleptic-free schizophrenic patients, one a preliminary dose-finding study and the other, an early efficacy trial.