Synthesis and Dopaminergic Properties of Benzo-Fused Analogues of Quinpirole and Quinelorane

Abstract

In an analogy to the potent catechol dopamine D1 agonists dihydrexidine (1) and dinapsoline (2), benzo rings were fused onto the structures of the dopamine D2-selective agonists quinelorane (3) and quinpirole (4). Each of the phenyl ring-substituted derivatives had significant affinity for D2 receptors, albeit somewhat lower than the two parent compounds, 3 and 4. Compounds with N-propyl and N-allyl substituents (5b, 5c, 6c, and 6d) had higher affinity for the D2 dopamine receptor than did their corresponding secondary amines (5a and 6a). Slightly different effects on affinity of an n-propyl and an n-allyl group in the new analogues of 3 and 4 suggest that different binding orientations may be invoked at the receptor.

Structural Modifications of Neuroprotective Anti-Parkinsonian (−)-N6-(2-(4-(Biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): An Effort toward the Improvement of in Vivo Efficacy of the Parent Molecule

“…50 It was hypothesized that in both cases H-bonding interaction of the parent amino group with serine-192 at the DA receptor should be maintained. 51 Specifically, the (−) isomer of 5-hydroxy aminotetraline was synthesized, as we have shown in our previous reports that the (−)-enantiomer exhibits the highest affinity compared to the (+)-isomer for both D 2 and D 3 receptors.…”

Modulation of Heroin and Cocaine Self-Administration by Dopamine D1- and D2-Like Receptor Agonists in Rhesus Monkeys

“…To investigate D1-like receptor mechanisms, we chose the representative agonists SKF 82958 and SKF 81297, both of which show high affinity for D1-like receptors in rhesus monkey brain as well as approximately 20-(SKF 82958) to 1000-fold (SKF 81297) selectivity for D1-like versus D2-like receptors (Weed et al, 1998). To investigate D2-like mechanisms, we chose the representative agonists R-(Ϫ)-propylnorapomorphine (NPA) and quinpirole, both of which have very high degrees of selectivity for D2-like versus D1-like receptors (i.e., Ͼ400-fold; Gao et al, 1990;Doll et al, 1999). In addition, NPA has been shown to exhibit relatively high affinity at the D2-like receptor in binding studies with rhesus monkey brain, whereas quinpirole, but not NPA, has modest selectivity for D 3 compared with D 2 receptor subtypes (Malmberg and Mohell, 1995;Ranaldi et al, 2001).…”

Neurotoxins and medicinals for the treatment of Parkinson’s disease. Part 2: dopamine receptors and their agonists

“…The D 2 , D 3 -agonist quinelorane ((5aR-trans)-5,5a,6,7,-8,9,9a,10-octahydro-6-propylpyridol[2,3]-quinazolin-2-amine, XXXIV) [45,57,61] is also structurally close to the aforementioned tricyclic derivatives. [35,105] and more effectively influences the locomotor activity than do ergoline agonists (e.g., pergolide) [110].…”

“…Additional factors can be the structure of aromatic substitu-ents and the distance from oxygen atoms of hydroxy groups or other electronegative centers to the positively charged nitrogen atom [44 -47], which is typically within 5.5 -7.4 Å [48]. It was also suggested [45,49,50] that the affinity to D 2 increase upon the introduction of N-propyl or N-allyl residues.…”