Specific dopamine D-1 and DA1 properties of 4-(mono- and -dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and its tetrahydrothieno[2,3c]pyridine analog

Abstract

The title compounds were prepared and examined to elucidate further the structure-activity relationships of dopamine agonists related to nomifensine. Two of the compounds, 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline and 4-(3,4-dihydroxyphenyl)-1,2,3,4-tetrahydrothieno[2,3-c]pyridine, have been reported in the patent literature. In stimulation of rat retinal adenylate cyclase, a measure of dopamine D-1 agonist activity, the tetrahydroisoquinoline was about equipotent to dopamine. The thienyl isostere had nearly twice the potency. Both compounds were potent vasodilators in the canine renal artery, producing dilation through stimulation of DA1 type peripheral dopamine receptors. A monohydroxy analogue, 4-(3-hydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline, had only slight activity in the cyclase assay and was inactive in the canine renal artery. These results, combined with those from an earlier study, demonstrate that N-alkylation decreases both dopamine D-1 and DA-1 agonist potency, with activity ordered as H greater than methyl greater than ethyl greater than propyl. The results also demonstrate the necessity for the catechol function in this series.

Identification of a 2-phenyl-substituted octahydrobenzo[f]quinoline as a dopamine D3 receptor-selective full agonist ligand

“…Moreover, previous published literature studies have shown that N -alkylation of the ethylamine moiety enhances D 2 over D 1 receptor agonist selectivity, and D 2 receptor affinity is optimized with an n -propyl substitution. 18–20 Thus, we selected analog 5b , which demonstrated the highest D 2 selectivity and affinity within the library, and synthesized its n-propyl analog 5f (Scheme 3) for further pharmacological evaluation.…”

Dopamine Agonists in the Treatment of Parkinsons Disease-Past, Present and Future

“…Furthermore labeled SKF-38393 is displaced by the selective D 1 antagonist SCH-23390 from rat striatum, but not with selective D 2 agonist such as quinpirole nor antagonist sulpiride [108]. later in 1987, Nichols further elucidated the structure-activity-relationship of a series of tetrahydroisoquinolines, including the bioisosteric effect of the thienyl analogs [110]. In the same year, Andersen reported several thienopyridine derivatives as selective dopamine D 1 receptor agonists with full dopamine efficacy [111].…”

“…Indeed, changing the 3,4-dihydroxy aryl group to the 3-monohydroxy phenyl rendered the target molecule inactive in adenylate cyclase stimulation [110]. In addition to this critical catechol structure, it was also discovered that the nitrogen atom in the tetrahydroisoquinoline can barely tolerate a small methyl group, bulkier groups such as ethyl or propyl have detrimental effects towards cyclase function presumably due to the adoption of a misfitted conformation thus preventing efficient binding to its corresponding receptors.…”

An Efficient Synthesis of 4-Aryl-1,2,3,4-Tetrahydroisoquinolines

“…Thus, the most active tetrahydroisoquinoline, as measured by stimulation of rat retinal adenylate cyclase, was racemic 4-(3',4'-dihydroxyphenyl)-1,2,3,4-tetrahydroisoquinoline 0 . 2 In this paper, we present a short, efficient synthesis of 1 and the related N-methyld-phenyl-1,2,3,4-tetrahyrdoisuquinoline (2). Our approach, which should be quite general for this class of compounds, *To whom correspondence should be addressed.…”

“…Thus, 4-phenylisoquinoline Q) was converted to N-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinohe (2) in 85% overall yield by first methylating with methyl triflate and then reducing with sodium cyanoborohydride. When the triflate salt 6 CH3 OTf CH2CI2…”