Conformational and MO studies of hydroxy‐2‐aminotetralins

Abstract

Attempting to explain'the differences in the pharmacological profiles of the isomeric monohydroxyand dihydroxy-2-aminotetralins (DHAT) which are potent dopaminergic agonists we have calculated the conformational energies of 2-aminotetralin and its N,N-dipropyl derivative using the QCFF/Pi and PCILO methods. Molecular electrostatic potential (MEP) maps based on ab initio wave functions were computed for both dihydroxytetralins. Root-mean-square (rms) deviations from steric congruence between the enantiomeric $6-and 6,7-DHAT based either on atomic centers or on the minima in MEP near the putative points of attachment to the receptor are small, but may nevertheless be sufficient to cause differences in activity on subtypes of the dopamine receptor. N,N-dipropyl substitution influences the conformational energies of the skeleton and the preferences in the orientation of the propyl groups in the isomeric DHAT may be important for the interaction with the receptor. The HOMO energies of the isomeric HAT and DHAT do not correlate with their potencies.

Conformationally defined adrenergic agents. 15. Conformationally restricted and conformationally defined tyramine analogs as inhibitors of phenylethanolamine N-methyltransferase

“…The conformations of 2-aminotetralin derivatives have been studied by NMR,28 X-ray crystallography,29 and theoretical calculations. 30 The half-chair conformation for the cyclohexene portion of 2-aminotetralin derivatives is lower in energy than the half-boat conformation by 3-5 kcal/mol.30 The conformationally defined tyramine ana-logues 22-24 with a half-chair 2-aminotetralin moiety were better inhibitors of PNMT than were the conformationally defined half-boat 2-aminotetralin analogues 17-20. Apparently, the half-chair conformation for the 2-aminotetralin system is preferred by the enzyme.…”

“…Besides the benzobicyclo[2.2.1]hept-2-ylamine (e.g. 17-21 and [30][31][32][33] and the benzobicyclo[3.2.1] octylamine (e.g. 22-25 and 34-36), we have used other conformationally defined benzobicyclic systems in our studies.…”

“…3-(2-Methoxyphenyl)cyclopentanone (42). By the same procedure as described for 40, 42 (3.35 g, 58.8% yield) was obtained from 2-cyclopentenone (2.46 g, 30 mmol) and 2-bromoanisole (39) as a colorless oil: bp 110-115 °C (bulb-to-bulb distillation, 0.5 mm); IR (neat) 2961, 2838,1744,1601,1495,1244,1028,754 cm"1; NMR (CDC13) 7.19 (m, 2 ), 6.90 (m, 2 H), 3.82 (s, 3 H, CHgO), 3.67 (m, 1 H), 2.62 (dd, J = 8, 19 Hz, 1 H), 2.S-2.2 (m, 4 ), 2.05 (m, 1 H); 13C NMR (CDClg) 219.12 (C=0), 157.22,130.97,127.49,126.42,120.36,110.30,54.98 (CHgO), 44.34, 38.48, 36.57, 28.89; mass spectrum, m/z (relative intensity) 191 (19), 190 (100, M+), 161 (15), 159 (14), 147 (19), 134 (51), 119 (67), 91 (88). Anal.…”

Synthesis and pharmacological evaluation of the individual stereoisomers of 3-[methyl(1,2,3,4-tetrahydro-2-naphthalenyl)amino]-1-indanone, a potent mast cell stabilising agent

“…Previous NMR and X ray studies on 2-aminotetralin derivatives have shown that introduction of an amino substituent alters the symmetry of the tetralin aliphatic ring, producing up to eight different possible conformations. 12,13 It has been demonstrated that the half boat arrangement of the non aromatic region of 2-aminotetralin derivatives is lower in energy than the half chair conformation. 12, 14-16…”

The Electronic Structure of Dopamine. An ab initio Electrostatic Potential Study of the Catechol Moiety

“…[12] [ 14-1 81). Dopaminergic compounds were also studied [ 191 [20]; thus the aromatic regions of 5,6-ADTN, 6,7-ADTN, and of the ergoline skeleton were compared, showing interesting similarities and differences. In the present study, we examine the electronic structure of the aromatic region of dopamine in various conformations.…”