Synthesis and Molecular Modeling of 1-Phenyl-1,2,3,4-tetrahydroisoquinolines and Related 5,6,8,9-Tetrahydro-13bH-dibenzo[a,h]quinolizines as D1 Dopamine Antagonists

Abstract

New 1-phenyl-1,2,3,4-tetrahydroisoquinolines and related 5,6,8,9-tetrahydro- 13bH-dibenzo[a,h]-quinolizines were prepared as ring-contracted analogs of the prototypical 1-phenyl-2,3,4,5-tetrahydrobenzazepines (e.g., SCH23390) as a continuation of our studies to characterize the antagonist binding pharmacophore of the D1 dopamine receptor. Receptor affinity was assessed by competition for [3H]SCH23390 binding sites in rat striatal membranes. The 6-bromo-1-phenyltetrahydroisoquinoline analog 2 of SCH23390 1 had D1 binding affinity similar to that for the previously reported 6-chloro analog 6, whereas the 6,7-dihydroxy analog 5 had significantly lower D1 affinity. Conversely, neither 6-monohydroxy- (3) nor 7-monohydroxy-1-phenyltetrahydroisoquinolines (4) had significant affinity for the D1 receptor. These results demonstrate that 6-halo and 7-hydroxy substituents influence D1 binding affinity of the 1-phenyltetrahydroisoquinolines in a fashion similar to their effects on 1-phenyltetrahydrobenzazepines. The conformationally constrained 3-chloro-2-hydroxytetrahydrodibenzoquinolizine 9 had much lower affinity relative to the corresponding, and more flexible, 6-chloro-7-hydroxy-1-phenyltetrahydroisoquinoline 6. Similarly, 2,3-dihydroxytetrahydrodibenzoquinolizine 10 had much lower D1 affinity compared to dihydrexidine 14, a structurally similar hexahydrobenzo[a]phenanthridine that is a high-affinity full D1 agonist. Together, these data not only confirm the effects of the halo and hydroxy substitutents on the parent nucleus but demonstrate the pharmacophoric importance of both the nitrogen position and the orientation of the accessory phenyl ring in modulating D1 receptor affinity and function. Molecular modeling studies and conformational analyses were conducted using the data from these new analogs in combination with the data from compounds previously synthesized. The resulting geometries were used to refine a working model of the D1 antagonist pharmacophore using conventional quantitative structure-activity relationships and three-dimensional QSAR (CoMFA).

Synthesis, DNA Binding and Antitumor Evaluation of Styelsamine and Cystodytin Analogues

“…[23] 85.0–86.0 °C); R f (5% MeOH/CH 2 Cl 2 ) 0.67; IR ν max (ATR) 3236, 2981, 1634, 1590, 1231 cm −1 ; 1 H NMR (CDCl 3 , 400 MHz) δ H 7.71–7.69 (2H, m, H-12 and H-16), 7.44 (1H, tt, J = 6.4, 1.2 Hz, H-14), 7.38–7.34 (2H, m, H-13 and H-15), 6.78 (1H, d, J = 8.0 Hz, H-8), 6.74–6.72 (2H, m, H-5 and H-9), 3.82 (3H, s, OMe), 3.79 (3H, s, OMe), 3.66 (2H, t, J = 7.2 Hz, H 2 -2), 2.85 (2H, t, J = 7.2 Hz, H 2 -3); 13 C NMR (CDCl 3 , 100 MHz) δ C 167.6 (C-10), 148.9 (C-6), 147.5 (C-7), 134.2 (C-11), 131.4 (C-14), 131.3 (C-4), 128.4 (C-13 and C-15), 126.8 (C-12 and C-16), 120.6 (C-9), 111.9 (C-5), 111.3 (C-8), 55.7 (OMe × 2), 41.3 (C-2), 35.1 (C-3); (+)-ESIMS m/z 286 [M + H] + ; (+)-HRESIMS [M + H] + 286.1437 (calcd. for C 17 H 20 NO 3 , 286.1438).…”

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

“…This very brief SAR analysis has demonstrated the prerequisite for high dopamine D 1 efficacy within this molecular framework to include: (a) presence of a catechol unit; (b) basic nitrogen atom; and (c) a phenyl ring (or its isostere) which is to be held in a spatial orientation imposed by the asymmetric absolute relationship with respect to the catechol and the basic nitrogen [121]. This information, along with the conformational mobile nature of 4-phenyl-1,2,3,4-tetrahydroisoquinoline led Nichols to develop novel rigid compounds that contained structural features required for dopamine activity in particular at the dopamine D 1 subtype.…”

Synthesis of 5‐phenyl‐5,6,7,8‐tetrahydro‐1,6‐naphthyridines and 5‐phenyl‐6,7,8,9‐tetrahydro‐5H‐pyrido[3,2‐c]azepines as potential D1 receptor ligands

“…When separation of water was finished, the reactions mixture was cooled to room temperature, washed twice with saturated aqueous sodium hydrogen carbonate, once with water, and dried over sodium sulfate. After removal of the solvent, the residue was crystallized from ethanol to yield 10 …”

“…For example, the D1 receptor antagonist SCH23390 (2) plays an important role as radio ligand in receptor binding studies [8,9]. The phenyltetrahydroisoquinoline derivative 3, its ring-contracted homolog, still possesses an antagonistic effect on D1 [10]. In contrast, Fenoldopam (4), a selective D1 agonist, is utilized in the United States to manage severe hypertensions [11] (Scheme 1).…”