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

GARIBOTTO, FRANCISCO MATÍAS; ANDÚJAR, SEBASTIÁN ANTONIO; PARRAVICINI, OSCAR; ENRIZ, RICARDO DANIEL; ROJAS, SEBASTIÁN; ANGELINA, EMILIO

San Miguel de Tucumán

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

Sociedad Argentina de Biofísica

p { margin-bottom: 0.25cm; line-height: 120%; }Dopaminereceptors (DR) ligands are potential drug candidates for treatingneurological disorders including schizophrenia or Parkinson?sdisease. Three series of isoquinolines:(E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl1,2,3,7,8,8a-hexahydrocyclopenta [ij]-IQs (HCPIQs) (series 2) and(E)-1-(prop-1-en-1-yl)-1,2,3,4- tetrahydroisoquinolines (series 3),were prepared to determine their affinity for both D1 and D2 -likeDR. The effect of different substituents on the nitrogen atom (methylor allyl), the dioxygenated function (methoxyl or catechol), thesubstituent at the b -position of the THIQ skeleton, and the presenceor absence of the cyclopentane motif, were studied. We observed thatthe most active compounds in the three series (2c, 2e, 3a, 3c, 3e, 5cand 5e) possessed a high affinity for D2-like DR and these remarkablefeatures: a catechol group in the IQ-ring and the N-substitution(methyl or allyl). The series showed the following trend to D2 -RDaffinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, 321thesubstituent 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, 3cand 3e, respectively. Finally, and in agreement with the experimentaldata, molecular modeling studies on DRs of the most characteristicligands ofthe three series revealed stronger molecular interactions with D2 DRthan with D1 DR, which further supports to the encountered enhancedselectivity to D2 DR1.