dinapsoline and Glioma

The synthesis and preliminary pharmacological evaluation of 8,9-dihydroxy-1,2,3,11b-tetrahydrochromeno[4,3,2,-de]isoquinoline (5, now named dinoxyline) is described. This molecule was designed as a potential bioisostere that would conserve the essential elements of our beta-phenyldopamine D(1) pharmacophore (i.e., position and orientation of the nitrogen, hydroxyls, and phenyl rings). Previously, we have rigidified these elements using alkyl bridges, as exemplified in the dopamine D(1) full agonist molecules dihydrexidine (1) and dinapsoline (2). This approach has been modified and we now show that it is possible to tether these elements using an ether linkage. Preliminary pharmacology has revealed that 5 is a potent full D(1) agonist (K(0.5) <10 nM; EC(50)=30 nM), but also has high affinity for brain D(2)-like and cloned D(2) and D(3) receptors. Interestingly, whereas 1 and 2 and their analogues have only moderate affinity for the human D(4) receptor, 5 also has high affinity for this isoform. Moreover, although N-alkylation of 1 and 2 increases D(2) affinity, the N-allyl (15) and N-n-propyl (17) derivatives of 5 had decreased D(2) affinity. Therefore, 5 may be engaging different amino acid residues than do 1 and 2 when they bind to the D(2) receptor. This is the first example of a ligand with high affinity at all dopamine receptors, yet with functional characteristics similar to dopamine. These rigid ligands also will be useful tools to determine specific residues of the receptor transmembrane domains that are critical for agonist ligand selectivity for the D(4) receptor.

Topics: Animals; CHO Cells; Corpus Striatum; Cricetinae; Dopamine; Dopamine Agonists; Glioma; Humans; Isoquinolines; Ligands; Naphthols; Protein Isoforms; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2

Dinapsoline ((2); (+/-)-dihydroxy-2,3,7,11b-tetrahydro-1H-naphth[1,2,3-de]isoquinoline) is a full D(1) dopamine agonist that also has significant D(2) receptor affinity. Based on a similar pharmacophore, dinapsoline has pharmacological similarities to dihydrexidine ((1); (+/-)-trans-10,11-dihydroxy-5,6,6a,7,8,12b-hexahydrobenzo[a]phenanthridine), the first high affinity full D(1) agonist. Small alkyl substitutions on the dihydrexidine backbone are known to alter markedly the D(1):D(2) selectivity of dihydrexidine, and it was of interest to determine whether similar SAR exists within the dinapsoline series. This report describes the synthesis and pharmacological evaluation of six analogues of dinapsoline: N-allyl-(3);N-n-propyl- (4); 6-methyl- (5); 4-methyl- (6); 4-methyl-N-allyl- (7); and 4-methyl-N-n-propyl-dinapsoline (8). As expected from earlier studies with the dihydrexidine backbone, N-allyl (3) or N-n-propyl (4) analogues had markedly decreased D(1) affinity. Unexpectedly, and unlike the dihydrexidine series, these same substituents did not markedly increase D(2) affinity. The addition of a methyl group to position 6 (5) increased D(1):D(2) selectivity, but less markedly than did the analogous 2-methyl substituent added to 1. Unlike the analogous 4-methyl substituent of 1, the addition of a 4-methyl-group (6) actually decreased D(1) affinity without affecting D(2) affinity. These data demonstrate that the dinapsoline (2) backbone can be modified to produce dopamine agonists with novel properties. Moreover, as rigid ligands in which small substituents can cause significant changes in selectivity, they are important tools for deriving 'differential' SARs of the dopamine receptor isoforms.

Topics: Animals; Brain Neoplasms; Cell Membrane; Cloning, Molecular; Cyclic AMP; Cyclization; Dopamine Agonists; Glioma; In Vitro Techniques; Indicators and Reagents; Isoquinolines; Naphthols; Neostriatum; Radioligand Assay; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured