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

• Three series of isoquinolines were prepared and their affinity for DR determined.
• Substituent at β-position of the THIQ and presence of the cyclopentane were studied.
• The HCPIQs stood out for the unexpected affinity and selectivity towards D2-DR.
• None of the most active THIQs on D2 DR displayed a relevant cytotoxicity.
• Molecular modeling studies supported our SAR studies.

Dopamine receptors (DR) ligands are potential drug candidates for treating neurological disorders including schizophrenia or Parkinson’s disease. Three series of isoquinolines: (E)-1-styryl-1,2,3,4-tetrahydroisoquinolines (series 1), 7-phenyl-1,2,3,7,8,8a-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-like DR. The effect of different substituents on the nitrogen atom (methyl or allyl), the dioxygenated function (methoxyl or catechol), the substituent at the β-position of the THIQ skeleton, and the presence or absence of the cyclopentane motif, were studied. We observed that the most active compounds in the three series (2c, 2e, 3a, 3c, 3e, 5c and 5e) possessed a high affinity for D2-like DR and these remarkable features: a catechol group in the IQ-ring and the N-substitution (methyl or allyl). The series showed the following trend to D2-RD affinity: HCPIQs > 1-styryl > 1-propenyl. Therefore, the substituent at the β-position of the THIQ and the cyclopentane ring also modulated this affinity. Among these dopaminergic isoquinolines, HCPIQs stood out for unexpected selectivity to D2-DR since the Ki D1/D2 ratio reached values of 2465, 1010 and 382 for compounds 3a, 3c and 3e, respectively. None of the most active THIQs in D2 DR displayed relevant cytotoxicity in human neutrophils and HUVEC. Finally, and in agreement with the experimental data, molecular modeling studies on DRs of the most characteristic ligands of the three series revealed stronger molecular interactions with D2 DR than with D1 DR, which further supports to the encountered enhanced selectivity to D2 DR.

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