Synthesis and evaluation of non-catechol D-1 and D-2 dopamine receptor agonists: benzimidazol-2-one, benzoxazol-2-one, and the highly potent: benzothiazol-2-one 7-ethylamines

Abstract

Our interest in identifying D-1 and D-2 dopamine receptor agonists that are not catechols led us to extend previous studies with oxindoles by investigating analogues of dopamine, N,N-dipropyldopamine, m-tyramine, N,N-dipropyl-m-tyramine, and epinine in which the m-hydroxyl is replaced by the NH portion of a thiazol-2-one, oxazol-2-one, or imidazol-2-one group fused to the 2,3-position. These compounds were evaluated for their affinity and agonist activity at D-1 and D-2 receptors by using in vitro assays. Replacement of the m-hydroxy in N,N-dipropyldopamine with the thiazol-2-one group resulted in a dramatic increase in D-2 receptor affinity and activity compared to that of N,N-dipropyldopamine itself or that of the corresponding oxindole, 1. The resulting compound, 7-hydroxy-4-[2-(di-n-propylamino)ethyl]benzothiazol-2(3H)-one (4), is the most potent D-2 receptor agonist reported to date in the field-stimulated rabbit ear artery (ED50 = 0.028 nM). The benzoxazol-2-one (6), benzimidazol-2-one (5), and isatin (51) analogues showed D-2 receptor agonist potency similar to that of 1. The des-7-hydroxyl analogue of 4 (21) also has enhanced D-2 receptor activity compared to that of the corresponding oxindole, 8. 7-Hydroxy-4-(2-aminoethyl)benzothiazol-2(3H)-one, 27, a non-catechol, has enhanced D-1 and D-2 receptor activity in vitro compared to that of the corresponding oxindole, 7. In vivo, 27 increased renal blood flow and decreased blood pressure in the dog. However, these effects were mediated primarily by D-2 receptor agonist activity. This may be a result of the D-1 partial agonist activity of 27 coupled with its potent D-2 receptor activity.

Five‐Membered Heterocycles: 1,3‐Azoles

“…For this reason, good reagents are phosgene [495], urea [496],carbonyldiimidazole [497], dimethyl carbonate [498], N,N-diethylcarbamyl chloride and carbon dioxide [499].…”

SK&F 89124, A POTENT AND SELECTIVE AGONIST AT PREJUNCTIONAL DOPAMINE RECEPTORS

“…Functional experiments in the rabbit isolated splenic artery show that SK&F 89124 has no significant DA, receptor mediated effect on vascular smooth muscle (Ohlstein et al, unpublished data). Although SK&F 89124 has some activity as a renal vasodilator in vivo (Huffman et al, 1983), this could be a consequence of its DA, mediated sympatholytic effect (Lokhandwala and Jandhyala, 1977;Weinstock et al, 1987).…”

The identification of 7-[(R)-2-((1S,2S)-2-benzyloxycyclopentylamino)-1-hydroxyethyl]-4-hydroxybenzothiazolone as an inhaled long-acting β2-adrenoceptor agonist

“…14 The 4-hydroxybenzothiazolone catechol mimetic was first described in a series of dopamine receptor (DR) agonists, 15 and DR activity was identified to be the most significant off-target activity for the series 5 and 6 following screening versus an internal panel of enzymes and receptors. 16 For the most interesting analogues functional b 2 AR potency and efficacy, onset of action (OoA) and duration of action (DoA) were then assessed in an electrically stimulated superfused guinea-pig tracheal-strip assay as described previously.…”