Thiazoloindans and Thiazolobenzopyrans:  A Novel Class of Orally Active Central Dopamine (Partial) Agonists

Abstract

The 2-aminothiazole moiety has proven its value in medicinal chemistry as a stable and lipophilic bioisosteric replacement of a phenol group. This approach has provided dopamine (DA) agonists with good oral availability. To further explore its use in the development of DA agonists, we have combined the 2-aminothiazole moiety with 2-aminoindans and 3-aminobenzopyrans, which are known templates for DA agonists. In this study we have synthesized 6-amino-3-(N,N-di-n-propylamino)-3,4-dihydro-2H-thiazolo[5, 4-f]-[1]benzopyran (12) and 6-amino-2-(N, N-di-n-propylamino)thiazolo[4,5-f]indan (20) and several analogues (13, 17, and 21). The affinity of the thiazolobenzopyrans and thiazoloindans for DA receptors was evaluated, which revealed compound 20 to have high affinity for DA D(3) receptors. In addition, the compounds were screened for their potential to inhibit lipid peroxidation, to determine their radical scavenging properties. Compounds 12, 20, and 21 were subjected to further pharmacological evaluation in a functional assay to determine intrinsic activity. Compound 20 was also studied with microdialysis (to determine effects on DA turnover in striatum) and in unilaterally 6-OH-DA lesioned rats (to determine their potential as DA agonists). These studies selected compound 20 (GMC 1111) as particularly interesting. Compound 20 caused a rotation activation in unilaterally 6-OH-DA lesioned rats and an increase in DA turnover in rat striatum. This dual agonist/antagonist action is best accounted for by its partial agonism at striatal DA D(2) receptors. Interestingly, 20 displayed long-lasting activity and excellent oral availability in 6-OH-DA lesioned rats, making this compound potentially useful for the treatment of Parkinson's disease.

Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D3 Receptor Ligands

“…The heteroaromatic derivatives 69 and 70, which are precursors for compounds 29 and 30, respectively, were obtained by modified Pictet ± Spengler reactions (Scheme 8). [27,28] The aminothiazole scaffold, a proposed phenol bioisostere in compound 31, [29] was available by Hantzsch thiazole synthesis. [30] Scheme 8.…”

A Multi‐Component Reaction in the Morita­–Baylis–Hillman Route

“…[19] Thiochromenes are a biologically important class of compounds exhibiting anti-inflammatory, [20] anti-HIV, [21] antibacterial, [22] antihyperplasia, [23] antipsychotic, [24] anticancer, and analgesic [25] activities. This indicates that the unsaturated enoate moiety at the ortho-position itself provides sufficient activation for the S N Ar reaction.…”

Dopamine D3 Receptor Ligands with Antagonist Properties

“…Representing the N , N ‐dipropyl‐indan‐2‐amine group, known from D 3 receptor active compounds like pramipexole, compound 22 (GMC 1111) was attributed to a 2‐aminothiazole moiety, which is a stable and lipophilic bioisosteric replacement of a phenol/catechol group (Scheme ) 63. In functional mitogenesis assays both agonist and antagonist action was observed, combined with high oral bioavailability and long‐lasting activity in rats.…”

“…Compound 22 (GMC 1111; Scheme ) exhibited a mixed dopamine receptor agonist/antagonist profile in functional assays 63. In rats unilaterally lesioned with 6‐hydroxydopamine (6‐OH‐DA) it caused an activation of rotation, which was suggestive of agonism at postsynaptic dopamine receptors.…”