A New Type of Prodrug of Catecholamines:  An Opportunity to Improve the Treatment of Parkinson's Disease

Abstract

After decades of research around dopamine agonists, we have found a promising compound in S-PD148903 that represents a new type of prodrug, which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT, known to display mixed dopamine D(1)/D(2) receptor agonist properties just like apomorphine. This prodrug has an enone structure which by an oxidative bioactivation mechanism is converted to the corresponding catechol and is delivered enantioselectively into the CNS. This novel concept has the potential to revolutionize the treatment of Parkinson's disease by competing with L-DOPA, the current treatment of choice.

Antiparkinson Prodrugs

“…proposed the synthesis and pharmacological evaluation of the orally active enone prodrug S-(-)-6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one [(-)- 114 (S-PD148903)]. 1-4 Bioactivation of enones by metabolic conversion to their corresponding catecholamines, as was demonstrated for (-)- 114 , is thought to be the general bioactivation mechanism ( Figure 19 ) [ 85 , 86 , 87 ]. Compound S-PD148903 represents a new type of prodrug which in the rat is bioactivated to the catecholamine S-5,6-diOH-DPAT ( 115 ), known to display mixed DA D1/D2 receptor agonist properties just like apomorphine.…”

Orally Active Analogues of the Dopaminergic Prodrug 6-(N,N-Di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one: Synthesis and Pharmacological Activity

“…Condensation of N -methyl- N - n -propylamine, N -ethyl- N - n -propylamine, or N -methyl- N -propargylamine with precursor 7 required heating in a sealed flask in the presence of powdered 4 Å molecular sieves. As reported in the synthesis of (−)- 6 , it was preferred to proceed with the reduction of the enamine without purification. , Yields were moderate since the selectivity for reduction of the desired double bond was difficult to control. Use of methanol or 1,2-dichloroethane as solvent increased reaction speed but decreased selectivity. , In tetrahydrofuran the selectivity of the reaction could be controlled by maintaining slightly acidic conditions at a low temperature.…”

“…Recently, we described the synthesis and pharmacological evaluation of S -(−)-6-( N , N -di- n -propylamino)-3,4,5,6,7,8-hexahydro-2 H -naphthalen-1-one ((−)- 6 ), an orally active prodrug of the mixed DA D 1 /D 2 agonist (−)- 2 (Scheme ). − This prodrug was found to be efficacious in vivo in models for Parkinson's disease in the rat. Because many N -(alkylhydroxy)-2-aminotetralins are known to act as DA agonists (Table ), we decided to synthesize a series of racemic analogues of 6 with different N-substituents. ,, Further, a fluorinated analogue of 6 was prepared as a potential ligand for positron emission tomography (PET), aiming at a pharmacological effect similar to that of 6 .…”

Orally Active Oxime Derivatives of the Dopaminergic Prodrug 6-(N,N-Di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one. Synthesis and Pharmacological Activity

“…The synthesis and pharmacological evaluation of the orally active enone prodrug S -(−)-6-( N , N -di- n -propylamino)-3,4,5,6,7,8-hexahydro-2 H -naphthalen-1-one ((−) 1 ), and several of its analogues have been reported previously (Scheme ). − Bioactivation of enones by metabolic conversion to their corresponding catecholamines, as was demonstrated for (−)- 1 , is thought to be the general bioactivation mechanism. Catecholamines such as (−)-5,6-dihydroxy-2-( N , N -di- n -propylamino)tetralin ((−)-5,6-diOH-DPAT, (−)- 2 ) are known mixed dopamine (DA) D 1 /D 2 agonists with potential utility in the treatment of Parkinson's disease. − Prodrugs of such catecholamines may increase their usefulness by improving the bioavailability or extending the duration of action.…”

“…Although (±)- 1 displays no binding affinity for the DA D 1 and DA D 2 receptors, the binding affinity and functional effects of two oximes were evaluated at these receptors. , …”