Synthesis, conformation, and dopaminergic activity of 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines

Abstract

To probe the suggestion that D-1 (DA1) dopamine receptors might possess an accessory pi-binding site in a location complementary to a suitably oriented aromatic ring (i.e., in an axial orientation approximately orthogonal to the catechol nucleus) in agonists such as 2,3,4,5-tetrahydro-1-phenyl-1H-3-benzazepine-7,8-diol (1) and 3',4'-dihydroxynomifensine (2) that are selective for this subtype, cis- and trans-2,3,4,8,9,9a-hexahydro-4-phenyl-1H-indeno[1,7-cd]azepine-6,7-diol were prepared. These compounds are 5,6-ethano-bridged derivatives of the D-1 selective dopamine receptor agonist 1. Introduction of the bridge reduces the conformational mobility of the parent molecule. Comprehensive conformational analyses by molecular mechanical methods indicated that both the cis and trans isomers could attain a conformation that places the phenyl substituent in an axial orientation. X-ray analysis of the trans isomer showed an axial disposition of the phenyl ring; however, NMR studies suggest that this conformation is fixed in the trans isomer, but not in the cis. The dopamine receptor binding affinity and intrinsic activity of the cis isomer were considerably greater than those of its trans counterpart; the cis isomer also demonstrated a high degree of selectivity for the D-1 subtypes. One possible explanation of these results, suggested by the molecular modeling studies, is that both the axial orientation of the phenyl postulated to be required for binding to the receptor and a putatively requisite location of the nitrogen in approximately the plane of the catechol ring can be attained only by the cis isomer in which the tetrahydroazepine ring is in a twist conformation. Conversely, these results might simply suggest a preference of the D-1 receptors for benzazepine agonists having the phenyl group in an equatorial orientation. Still another possibility is that the D-1 receptor binding site is in a sterically hindered area accessible only to compounds that are relatively planar. However, it requires an axial 1-phenylbenzazepine for strong binding. Thus, a conformationally flexible cis isomer could more readily achieve the different conformations required to both gain access to and bind with the D-1 site.

Dopamine D1 receptor ligands: Where are we now and where are we going

“…47 These compounds possess a considerable degree of conformational mobility, and the optimum position of the phenyl ring for interaction with the proposed accessory binding site of the D 1 receptor (e.g., SCH-23390, 1) is likely to be equatorially. 48,49 There was a hypothesis that the preferred binding of benzazepine analogues to the D 1 receptor might be the consequence of a p-p non-bonded interaction between the C1-aromatic ring and a complementary residue of Phe, Tyr, or Trp on the receptor surface. 50 To probe the validity of such a concept, conformationally constrained benzazepines 8-10 were developed (Fig.…”

“…49 Compound cis-8 has a high affinity at the D 1 receptor with a K bind of 24 nM, whereas the trans-8 is inactive. However, similar to other benzazepine derivatives, this compound also shows partial agonist activity with only 62% of DA response.…”

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

“…The additional 1-phenyltetrahydroisoquinolines included herein were prepared by the procedure previously reported. 20 Briefly, the phenethylamine intermediates 16-19 were reacted with benzoyl chloride to afford the respective benzamides 20-23 that were then ring-closed via a Bischler-Napieralski cyclization28 to afford the 3,4-dihydroisoquinolines (24)(25)(26)(27). This was followed by reduction of the imine utilizing sodium borohydride to afford 28- C,H,N 0 No purification was necessary.…”

Chiral 1,1-diaryl compounds as important pharmacophores

“…65,66 The synthesis, conformation, and dopaminergic activity of related 5,6-ethano-bridged derivatives of selective dopaminergic 3-benzazepines has been examined. 67 In such studies, it was shown that the introduction of the bridge reduces the conformational mobility of the parent molecule, a feature which places the phenyl substituent in an axial orientation and which may be important for D 1 -agonist activity. 67 Moreover, a potent D A1 -receptor agonist with demonstrated renal vasodilator activity was found from a research programme investigating the effects of catechol ring uorination on cardiovascular and renal activities of fenoldopam enantiomers.…”