10 Reproduced from reference 10: Sesack SR. Synaptology of … Partial dopamine agonists In the 1980s we became interested in (-)-3-(3-hydroxyphcnyl)-N-n-propylpipcridine (3-PPP, prcclamol) which has an

asymmetric carbon: (+)-3-PPP behaves as a full agonist, displaying a biphasic curve, first inhibiting then stimulating animal thorough locomotor activity, much like apomorphinc (Figure 4). This is due at least Inhibitors,research,lifescience,medical in part to the greater sensitivity of autoreceptors: when autoreceptors are stimulated, the dopaminergic system is inhibited by negative feedback. As the dose increases, Tivantinib postsynaptic receptors take over and the system becomes stimulated. The (-)enantiomer, on the other hand, is only a partial agonist, meaning that it. has an agonist effect on the highly responsive autoreceptors but an antagonistic effect on postsynaptic receptors (although achieving some Inhibitors,research,lifescience,medical stimulation in the absence of dopamine). This intrinsic activity explains why 3-PPP exhibits not, only antipsychotic12 but, also antiparkinsonian properties.13 Figure 4. Effect of (+)- and (-)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) on rat locomotor activity, sc, subcutaneous. Figure 5 illustrates the differences between the effect, of antagonists and partial agonists on Inhibitors,research,lifescience,medical motor activation. A partial agonist will act, as an inhibitor in the presence of high

dopamine activity and as a stimulant in the presence of ver}’ low dopamine activity. The two activities meet at a level which represents the drug’s intrinsic activity. A partial agonist can thus be described as a “dopamine stabilizer.” In contrast, a pure antagonist, will inhibit to zero irrespective of the initial activity level, leading to catalepsy. A partial agonist, can thus act as an antipsychotic if it, has sufficiently low intrinsic Inhibitors,research,lifescience,medical activity. In schizophrenics (-)-3-PPP was an active antipsychotic but became ineffective after more than 1 week of treatment.13 The suggested explanation was that, its intrinsic activity was too high, making the autoreceptors subsensitive. It, was therefore predicted that agents with lower

intrinsic activity Inhibitors,research,lifescience,medical would have sustained antipsychotic activity. This proved to be precisely the case with aripiprazole, which was shown to be an effective antipsychotic with almost no extrapyramidal side effects. It also induced a slight but, significant decrease in prolactin. This is the profile expected of a partial dopamine receptor agonist. Anacetrapib Figure 5. Effect on psychomotor activation of partial agonists (right panel) versus pure antagonists (left panel).11 Reproduced from reference 11: Hjorth S, Carlsson A, Clark D, et al. Central dopamine receptor agonist and antagonist actions of the enantiomers … Dopamine stabilizers (or partial antagonists) Surprisingly, we found dopamine stabilizers that were similar to partial agonists, yet which proved to have zero intrinsic activity when tested on dopamine receptors in vivo (for review, see ref 14). Their zero intrinsic activity was particularly puzzling.