Dopaminergic isoquinolines with hexahydrocyclopenta[ij]-isoquinolines as D2-like selective ligands

ROJAS SEBASTIAN; ANGELINA EMILIO; PARRAVICINI OSCAR; ENRIZ RICARDO DANIEL; GARIBOTTO FRANCISCO MATIAS; ANDUJAR SEBASTIAN

Tucumán

Congreso; III Latin American Federation of Biophysical Societies (LAFeBS). IX IberoAmerican Congress of Biophysics XLV. Reunión Anual SAB 2016; 2016

Dopamine receptors (DR) ligands are potential drug candidates fortreating neurological disorders including schizophrenia or Parkin-son?s disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl 1,2,3,7,8,8a-hexahydro-cyclopenta [ij]-IQs (HCPIQs) (series 2) and (E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3), were prepared to determinetheir affinity for both D1 and D2 -like DR. The effect of different sub-stituents on the nitrogen atom (methyl or allyl), the dioxygenated func-tion (methoxyl or catechol), the substituent at the b -position of theTHIQ skeleton, and the presence or absence of the cyclopentane motif,were studied. We observed that the most active compounds in the threeseries (2c, 2e, 3a, 3c, 3e, 5c and 5e) possessed a high affinity for D2-likeDR and these remarkable features: a catechol group in the IQ-ring andthe N-substitution (methyl or allyl). The series showed the followingtrend to D2 -RD affinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, the substituent at the b -position of the THIQ and the cyclopentane ringalso modulated this affinity. Among these dopaminergic isoquinolines,HCPIQs stood out for unexpected selectivity to D2-DR since the KiD1/D2 ratio reached values of 2465, 1010 and 382 for compounds 3a,3c and 3e, respectively. Finally, and in agreement with the experimen-tal data, molecular modeling studies on DRs of the most characteristicligands of the three series revealed stronger molecular interactions withD2 DR than with D1 DR, which further supports to the encounteredenhanced selectivity to D2 DR1.