Gary Grunewald Research

Lab samples in glass tubes and bottles

Gary Grunewald Research

Gary Grunewald
Gary Grunewald Research

Research Overview—

Drug design using computer modeling and NMR techniques, mechanism of drug action in the central nervous system, enzyme inhibitors, and neurotransmitters.

Studies of the three-dimensional shape of drugs required for interaction with target sites (receptors, enzymes) have been a major focus of the work of Prof. Grunewald's research group. For many flexible drug molecules, one conformation is preferentially required for the desired action at a receptor site, and a different low-energy conformation is responsible for side effects through action at a second site.

Synthesis of analogues in which the molecular framework of the pharmacophore of the drug is "locked" into a conformationally-restricted (semi-rigid) or conformationally-defined (rigid) system allows a careful study of conformational aspects of drug action. In order to determine the function of epinephrine in the central nervous system, selective inhibitors of phenylethanolamine N-methyltransferase (PNMT) are required. Coupled with high-field NMR techniques, such as transferred nuclear Overhauser enhancements, and molecular modeling using computational techniques for pharmacophore delineation, a potent and selective inhibitor of epinephrine biosynthesis has recently been synthesized. It was necessary to simultaneously map the desired active site of the enzyme PNMT and the undesired competing binding site, the a2-adrenoceptor, to achieve this success.

Similar drug design approaches are underway for antidepressant drugs (neurotransmitter-selective reuptake inhibitors), anticancer drugs related to paclitaxel (Taxol ™), and NMDA receptor antagonists for the treatment of stroke.

Binding interactions in the active site of human PNMT with the inhibitor 7-N-(2,2,2-trifluoroethyl)-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (hPNMT K i = 23 nM). Details in text below.

The figure above illustrates the binding interactions in the active site of human PNMT with the inhibitor 7-N-(2,2,2-trifluoroethyl)-aminosulfonyl-3-hydroxymethyl-1,2,3,4-tetrahydroisoquinoline (hPNMT K i = 23 nM). Yellow lines indicate possible hydrogen bonds. Carbons are shown in white, nitrogens in blue, oxygens in red, and sulfur in yellow. This picture was developed using x-ray crystallographic and molecular modeling techniques.

Selected Publications —

From Research at the University of Kansas

  1. Drinkwater, N.; Vu, H.; Lovell, K. M.; Criscione, K. R.; Collins, B. M.; Prisinzano, T. E.; Poulsen, S.-A.; McLeish, M. J.; Grunewald, G. L.; Martin, J. L. “Fragment-screening by X-ray Crystallography, Mass Spectrometry and Isothermal Titration Calorimetry to Identify PNMT Inhibitors.” Biochem. J. 431, 51–61 (2010).
  2. Drinkwater, N.; Gee, C. L.; Puri, M.; Criscione, K. R.; McLeish, M. J.; Grunewald, G. L.; Martin, J. L. “Molecular recognition of physiological substrate noradrenaline by the adrenaline synthesising enzyme PNMT and factors influencing its methyltransferase activity.” Biochem. J. 422, 463–471 (2009).
  3. Wu, Q.; Caine, J. M.; Thomson, S. A.; Slavica, M.; Grunewald, G. L.; McLeish, M. J. “Time-dependent inactivation of human phenylethanolamine N-methyltransferase by 7-isothiocyanatotetrahydro­isoquinoline.” Bioorg. Med. Chem. Lett. 19, 1071–1074 (2009).
  4. Bowman-James, K.; Grunewald, G. L.; Hanzlik, R. P. “Eulogy to Mathias P. Mertes, 1932–1989.” Med. Res. Rev. 29, 1–2 (2009).
  5. Grunewald, G. L.; Seim, M. R.; Bhat, S. R.; Wilson, M. E.; Criscione, K. R. “Synthesis of 4,5,6,7‑Tetrahydrothieno[3,2-c]pyridines and Comparison with Their Isosteric 1,2,3,4-Tetrahydro­isoquinolines as Inhibitors of Phenylethanolamine N-Methyltransferase.” Bioorg. Med. Chem. 16, 542–559 (2008).
  6. Gee, C. L.; Drinkwater, N.; Tyndall, J. D. A.; Grunewald, G. L.; Wu, Q.; McLeish, M. J.; Martin, J. L. “Enzyme Adaptation to Inhibitor Binding: A Cryptic Binding Site in Phenylethanolamine N-Methyltransferase.” J. Med. Chem. 50, 4845–4853 (2007).
  7. Grunewald, G. L.; Seim, M. R.; Regier, R. C.; Criscione, K. R. “Exploring the Active Site of Phenylethanolamine N-Methyltransferase with 1,2,3,4-Tetrahydrobenz[h]isoquinoline Inhibitors.” Bioorg. Med. Chem. 15, 1298–1310 (2007).
  8. Grunewald, G. L.; Seim, M. R.; Regier, R. C.; Martin, J. L.; Gee, C. L.; Drinkwater, N.; Criscione, K. R. “Comparison of the Binding of 3-Fluoromethyl-7-sulfonyl-1,2,3,4-tetrahydroisoquinolines with Their Isosteric Sulfonamides to the Active Site of Phenylethanolamine N-Methyltransferase.” J. Med. Chem. 49, 5424–5433 (2006).
  9. Grunewald, G. L.; Seim, M. R.; Lu, J.; Makboul, M.; Criscione, K. R. “Application of the Goldilocks Effect to the Design of Potent and Selective Inhibitors of Phenylethanolamine N-Methyltransferase: Balancing pKa and Steric Effects in the Optimization of 3-Methyl-1,2,3,4-tetrahydroisoquinoline Inhibitors by β-Fluorination.” J. Med. Chem. 49, 2939–2952 (2006).
  10. Gee, C. L.; Tyndall, J. D. A.; Grunewald, G. L.; Wu, Q.; McLeish, M. J.; Martin, J. L. “Mode of Binding of Methyl Acceptor Substrates to the Adrenaline-Synthesizing Enzyme Phenylethanolamine N-Methyltransferase: Implications for Catalysis.” Biochemistry, 44, 16875–16885 (2005).
  11. Wu, Q.; Gee, C. L.; Lin, F.; Tyndall, J. D.; Martin, J. L.; Grunewald, G. L.; McLeish, M. J. “Structural, Mutagenic, And Kinetic Analysis of the Binding of Substrates and Inhibitors of Human Phenylethanolamine N-Methyltransferase.” J. Med. Chem., 48, 7243–7252 (2005).
  12. Grunewald, G. L.; Lu, Jian; Criscione, K. R.; Okoro, C. “Inhibitors of Phenylethanolamine N-Methyl­transferase Devoid of α2-Adrenoceptor Affinity.” Bioorg. Med. Chem. Lett., 15, 5319–5323 (2005).
  13. Gee, C. L.; Nourse, A.; Hsin, A-Y.; Wu, Q.; Tyndall, J. D.; Grunewald, G. L.; McLeish, M. J.; Martin, J. L. “Disulfide-Linked Dimers of Human Adrenaline Synthesizing Enzyme PNMT are Catalytically Active.” Biochim. Biophys. Acta, 1750, 82–92 (2005).
  14. Grunewald, G. L.; Romero, F. A.; Chieu, A. D.; Fincham, K. J.; Bhat, S. R.; Criscione, K. R. “Exploring the Active Site of Phenylethanolamine N-Methyltransferase: 3-Alkyl-7-substituted-1,2,3,4-tetrahydroisoquinoline Inhibitors,” Bioorg. Med. Chem., 13, 1261–1273 (2005).
  15. Grunewald, G. L.; Romero, F. A.; Seim, M. R.; Criscione, K. R. Deupree, J. D.; Spackman, C. C.; Bylund, D. B. “Exploring the Active Site of Phenylethanolamine N-Methyltransferase with 3-Hydroxyethyl- and 3-Hydroxypropyl-7-substituted-1,2,3,4-tetrahydroisoquinolines,” Bioorg. Med. Chem. Lett., 15, 1143–1147 (2005).
  16. Grunewald, G. L.; Romero, F. A.; Criscione, K. R. “3-Hydroxymethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline Inhibitors of Phenylethanolamine N-Methyltransferase that Display Remarkable Potency and Selectivity,” J. Med. Chem., 48, 134–140 (2005).
  17. Grunewald, G. L.; Romero, F. A.; Criscione, K. R. “Nanomolar Inhibitors of CNS Epinephrine Biosynthesis: (R)-(+)-3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines as Potent and Highly Selective Inhibitors of Phenylethanolamine N-Methyltransferase,” J. Med. Chem., 48, 1806–1812, (2005).
  18. Romero, F. A.; Vodonick, S. M.; Criscione, K. R.; McLeish, M. J.; Grunewald, G. L. “Inhibitors of Phenylethanolamine N-Methyltransferase That Are Predicted to Penetrate the Blood-Brain Barrier: Design, Synthesis and Evaluation of 3-Fluoromethyl-7-(N-substituted aminosulfonyl)-1,2,3,4-tetrahydroisoquinolines That Possess Low Affinity toward the α2-Adrenoceptor,” J. Med. Chem., 47, 4483–4493, (2004).
  19. Wu, Q.; Criscione, K. R.; Grunewald, G. L.; McLeish, M. J. “Phenylethanolamine N-Methyltransferase Inhibition: Re-evaluation of Kinetic Data,” Bioorg. Med. Chem. Lett., 14, 4217–4220 (2004).
  20. McMillan, F. M.; Archbold, J.; McLeish, M. J.; Caine, J. M.; Criscione, K. R.; Grunewald, G. L.; Martin, J. L. “Molecular Recognition of Sub-micromolar Inhibitors by the Adrenaline Synthesising Enzyme PNMT,” J. Med. Chem., 47, 37–44 (2004).
  21. Stone, E. A.; Grunewald, G. L.; Lin, Y.; Ahsan, R.; Rosengarten, H.; Kramer, H. K.; Quartermain, D. “Role of Epinephrine Stimulation of CNS α1-Adrenoceptors in Motor Activity in Mice,” Synapse, 49, 1, 67–76 (2003).
  22. Lankin, D. C.; Grunewald, G. L.; Romero, F. A.; Oren, I.; Snyder, J. P. “The NH—FC Dipole Orientation Effect for Pendent Exocyclic CH2F,” Org. Lett., 4, 3557–3560 (2002).
  23. J. Begun, M. J. McLeish, J. M. Caine, E. Palant, G. L. Grunewald and J. L. Martin. “Crystallization of PNMT, the Adrenaline-synthesizing Enzyme, is Critically Dependent on a High Protein Concentration,” Acta Cryst., D58, 314–315 (2002).
  24. J. L. Martin, J. Begun, M. J. McLeish, J. M. Caine, and G. L. Grunewald. “Getting the Adrenaline Going: Crystal Structure of the Adrenaline-Synthesizing Enzyme PNMT,” Structure, 9, 977–985 (2001).
  25. G. L. Grunewald, T. M. Caldwell, Q. Li, and K. R. Criscione. "Synthesis and Evaluation of 4-Fluoro-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazapines as Selective Inhibitors of Phenylethanolamine N‑Methyltransferase versus the α2-Adrenoceptor," J. Med. Chem., 44, 2849–2856 (2001).
  26. G. L. Grunewald, V. H. Dahanukar, and K. R. Criscione. "Effect of a 3-Alkyl-, 4-Hydroxy- and/or 8-Aromatic-substituent on the Phenylethanolamine N-Methyltransferase Inhibitory Potency and α2-Adrenoceptor Affinity of 2,3,4,5-Tetrahydro-1H-2-benzazepines," Bioorg. Med. Chem., 9, 1957–1965 (2001).
  27. G. L. Grunewald, M. J. McLeish, and K. R. Criscione. "Phenylethanolamine N-Methyltransferase Kinetics: Bovine versus Recombinant Human Enzyme," Bioorg. Med. Chem. Lett., 11, 1579–1582 (2001).
  28. T. C. Boge, M. Hepperle, D. G. Vander Velde, C. W. Gunn, G. L. Grunewald and G. I. Georg, "The Oxetane Conformational Lock of Paclitaxel: The Structural Analysis of D-Secopaclitaxel," Bioorg. Med. Chem. Lett., 9, 3041–3046 (1999).
  29. G. L. Grunewald, T. M. Caldwell, Q. Li, V. H. Dahanukar, B. McNeil and K. R. Criscione, "Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α2-Adrenoceptor," J. Med. Chem., 42, 4351–4361 (1999).
  30. G. L. Grunewald, T. M. Caldwell, Q. Li, M. Slavica, R. T. Borchardt, W. Wang and K. R. Criscione, "Synthesis and Biochemical Evaluation of 3-Fluoromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α2-Adrenoceptor," J. Med. Chem., 42, 3588–3601 (1999).
  31. G. L. Grunewald, T. M. Caldwell, Q. Li and K. R. Criscione, "Synthesis and Evaluation of 3-Trifluoromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of Phenylethanolamine N-Methyltransferase versus the α2-Adrenoceptor," J. Med. Chem., 42, 3315–3323 (1999).
  32. G. L. Grunewald, V. H. Dahanukar, B. Teoh and K. R. Criscione, "3,7-Disubstituted-1,2,3,4-tetrahydroisoquinolines Display Remarkable Potency and Selectivity as Inhibitors of Phenylethanolamine N-Methyltransferase versus the α2-Adrenoceptor," J. Med. Chem., 42, 1982–1990 (1999).
  33. G. L. Grunewald, T. M. Caldwell, V. H. Dahanukar, R. K. Jalluri and K. R. Criscione, "Comparative Molecular Field Analysis (CoMFA) Models of Phenylethanolamine N-Methyltransferase (PNMT) and the α2-Adrenoceptor: The Development of New, Highly Selective Inhibitors of PNMT," Bioorg. Med. Chem. Lett., 9, 481–486 (1999).
  34. G. L. Grunewald, T. M. Caldwell, Q. Li and K. R. Criscione, "1,3-Dimethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines as Probes for the Binding Orientation of Tetrahydroisoquinoline at the Active Site of Phenylethanolamine N-Methyltransferase," Bioorg. Med. Chem., 7, 869–880 (1999).
  35. G. L. Grunewald, V. H. Dahanukar, R. K. Jalluri and K. R. Criscione, "Synthesis, Biochemical Evaluation, and Classical and Three-Dimensional Quantitative Structure-Activity Relationship Studies of 7-Substituted-1,2,3,4-tetrahydroisoquinolines and Their Relative Affinities Toward Phenylethanolamine N-Methyltransferase and the α2-Adrenoceptor," J. Med. Chem., 42, 118–134 (1999).
  36. G. L. Grunewald, V. H. Dahanukar, T. M. Caldwell and K. R. Criscione, "Examination of the Role of the Acidic Hydrogen in Imparting Selectivity of 7-(Aminosulfonyl)-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) Towards Inhibition of Phenylethanolamine N-Methyltransferase vs. the α2-Adrenoceptor," J. Med. Chem., 40, 3997–4005 (1997).
  37. W.-J. Cho and G. L. Grunewald, "Design and Stereoselective Synthesis of Conformationally Constrained Analogues of Zimeldine," Arch. Pharm. Res., 19, 168–170 (1996).
  38. S. F. Victory, D. G. Vander Velde, R.K. Jalluri, G. L. Grunewald and G. I. Georg, “Relative Stereochemistry and Solution Conformation of the Novel Paclitaxel-like Antimitotic Agent Epothilone A,” Bioorg. Med. Chem. Lett., 6, 893–898 (1996).
  39. J. M. Caine, I. G. Macreadie, G. L. Grunewald and M. J. McLeish, “Recombinant Human Phenylethanolamine N-methyltransferase: Overproduction in E. coli, Purification and Characterisation,” Protein Expression & Purification, 8, 160–166 (1996).
  40. G. L. Grunewald, V. H. Dahanukar, P. Ching and K. R. Criscione, “Effect of Ring Size or an Additional Heteroatom on the Potency and Selectivity of Bicyclic Benzylamine-Type Inhibitors of the Enzyme Phenylethanolamine N-Methyltransferase,” J. Med. Chem., 39, 3539–3546 (1996).
  41. G. C. B. Harriman, R. K. Jalluri, G. L. Grunewald, D. G. Vander Velde, G. I. Georg and R. H. Himes, "The Chemistry of the Taxane Diterpene: Stereoselective Synthesis of 10-Deacetoxy-11,12-epoxypaclitaxel," Tetrahedron Lett., 36, 8909–8912 (1995).
  42. G. L. Grunewald and V. H. Dahanukar, "Synthesis of 3-Alkyl-8-substituted- and 4-Hydroxy-8-substituted-2,3,4,5-tetrahydro-1H-2-benzazepines," J. Heterocyclic Chem., 31, 1609–1617 (1994).
  43. K.-H. A. Czaplinski and G. L. Grunewald, "A Comparative Molecular Field Analysis Derived Model of the Binding of Taxol Analogues to Microtubules," Bioorg. Med. Chem. Lett., 4, 2211–2216 (1994).
  44. D. G. Vander Velde, G. I. Georg, G. L. Grunewald, C. W. Gunn and L. A. Mitscher, ""Hydrophobic Collapse" of Taxol and Taxotere Solution Conformations in Mixtures of Water and Organic Solvent," J. Am. Chem. Soc., 115, 11650–11651 (1993).
  45. R.-S. Tsai, P.-A. Carrupt, B. Testa, N. E. Tayar, G. L. Grunewald and A. F. Casy, "Influence of Stereochemical Factors on the Partition Coefficient of Diastereomers in a Biphasic Octan-1-ol/water System," J. Chem. Res. (S), 298-299 (1993); J. Chem. Res. (M), 1901–1909 (1993).
  46. G. I. Georg, S. R. Gollapudi, G. L. Grunewald, C. W. Gunn, R. H. Himes, B. K. Rao, X.-Z. Liang, Y. W. Mirhom, L. A. Mitscher, D. G. Vander Velde, and Q.-M. Ye, "A Reinvestigation of the Taxol Content of Himalayan Taxus wallichiana Zucc. and a Revision of the Structure of Brevifoliol," Bioorg. Med. Chem. Lett., 3, 1345–1348 (1993).
  47. G. L. Grunewald, N. Skjærbæk and J. A. Monn, "An Active Site Model of Phenylethanolamine N-Methyltransferase Using CoMFA," in Trends in QSAR and Molecular Modelling ’92, C. G. Wermuth, Editor (ESCOM Science Publishers B. V., Leiden), 1993, pp. 513–516.
  48. G. L. Grunewald, M. S. S. Palanki and D. Vander Velde, "Use of Transferred Nuclear Overhauser Effects to Determine the Conformation of 1-(3,4-Dichlorophenyl)-2-aminopropane When Bound to the Active Site of Phenylethanolamine N-Methyltransferase (PNMT)," Bioorg. Med. Chem. Lett., 2, 1681–1684 (1992).
  49. G. L. Grunewald, V. M. Paradkar, D. M. Stillions and F. Ching, "A New Procedure for Regioselective Synthesis of 8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046) and its 3-Methyl Analogue as Inhibitors of Phenylethanolamine N-Methyltransferase (PNMT)," J. Heterocyclic Chem., 28, 1587–1592 (1991).
  50. G. L. Grunewald and V. M. Paradkar, "A Regioselective Synthesis of 8,9-Dichloro-2,3,4,5-tetrahydro-1H-2-benzazepine (LY134046), a Potent Phenylethanolamine N-Methyltransferase Inhibitor," Bioorg. Med. Chem. Lett.., 1, 59–60 (1991).
  51. G. L. Grunewald, M. S. S. Palanki and F. Takusagawa, "Structures of exo-2-Formamido-1,4-epoxy-1,2,3,4-tetrahydro-8-trifluoromethylnaphthalene and exo-2-Formamido-1,4-epoxy-1,2,3,4-tetrahydro-6-trifluoromethylnaphthalene," Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C47, 771–775 (1991).
  52. G. L. Grunewald, A. J. Kolar, M. S. S. Palanki, V. M. Paradkar, T. J. Reitz and D. J. Sall, "One-step Synthesis of Trifluoromethyl- and of Methoxy-substituted Benzyne Precursors," Org. Prep. Proced. Int., 22, 747–753 (1990).
  53. W. J. Brouillette, G. L. Grunewald, G. B. Brown, T. M. DeLorey, M. S. Akhtar, and G. Liang, "Sodium Channel Binding and Anticonvulsant Activities for the Enantiomers of a Bicyclic 2,4-Oxazolidinedione and Monocyclic Models, " J. Med. Chem., 32, 1577–1580 (1989).
  54. G. L. Grunewald, Q. Ye, D. J. Sall, K. R. Criscione and B. Wise, "Conformational and Steric Aspects of Phenylethanolamine and Phenylethylamine Analogues as Substrates or Inhibitors of Phenylethanolamine N-Methyltransferase," Mol. Pharmacol., 35, 93–97 (1989).
  55. Q. Ye and G. L. Grunewald, "Conformationally Restricted and Conformationally Defined Tyramine Analogues as Inhibitors of Phenylethanolamine N-Methyltransferase," J. Med. Chem., 32, 478–486 (1989).
  56. S. M. Knepper, G. L. Grunewald and C. O. Rutledge, "Inhibition of Norepinephrine Transport into Synaptic Vesicles by Amphetamine Analogs," J. Pharmacol. Exp. Ther., 247, 487–494 (1988).
  57. G. L. Grunewald and Q. Ye, "Stereochemical Aspects of Phenylethanolamine Analogues as Substrates of Phenylethanolamine N-Methyltransferase," J. Med. Chem., 31, 1984–1986 (1988).
  58. W. J. Brouillette, G. B. Brown, T. M. DeLorey, S. S. Shirali and G. L. Grunewald, "Anticonvulsant Activities of Phenyl-substituted Bicyclic 2,4-Oxazolidinediones and Monocyclic Models. Comparison with Binding to the Neuronal Voltage-dependent Sodium Channel," J. Med. Chem., 31, 2218–2221 (1988).
  59. G. L. Grunewald and Q. Ye, "Synthesis of Benzobicyclo[3.2.1]octanes Involving Inversion of Configuration via an N to O Acetyl Migration," J. Org. Chem., 53, 4021–4026 (1988).
  60. T. Högberg, S. Ross, P. Ström, G. L. Grunewald, M. W. Creese and J. D. Bunce, "Homoallylic Amines Related to Zimeldine. A Comparative Study on Neuronal Serotonin and Norepinephrine Reuptake Based on Conformational Analysis," J. Med. Chem., 31, 913–919 (1988).
  61. G. L. Grunewald, M. W. Creese and H. J. R. Weintraub, "Conformational Preferences in Alkylbenzenes and Aryl-alkylamines: A Comparative Study Using CAMSEQ, MM2 and Molecular Dynamics Methods," J. Comput. Chem., 9, 315–326 (1988).
  62. G. L. Grunewald, D. J. Sall and J. A. Monn, "Synthesis and Evaluation of 3-Substituted Analogues of 1,2,3,4-Tetrahydroisoquinoline as Inhibitors of Phenylethanolamine N-Methyltransferase (PNMT)," J. Med. Chem., 31, 824–830 (1988).
  63. G. L. Grunewald, D. J. Sall and J. A. Monn, "Conformational and Steric Aspects of the Inhibition of Phenylethanolamine N-Methyltransferase (PNMT) by Benzylamines," J. Med. Chem., 31, 433–444 (1988).
  64. G. L. Grunewald, J. A. Monn and D. J. Sall, "Approaches to the Design of Selective Inhibitors of Phenylethanolamine N-Methyltransferase (PNMT). Development of an Active Site Model for PNMT," in "Proceedings of the International Symposium on Brain Epinephrine," edited by J. Stolk, D. U’Prichard and K. Fuxe (Oxford Press, London), 1988, pp. 117–140.
  65. G. L. Grunewald, Q. Ye, L. Kieffer and J. A. Monn, "Conformational Requirements of Substrates for Activity with Phenylethanolamine N-Methyltransferase (PNMT)," J. Med. Chem., 31, 169–171 (1988).
  66. G. L. Grunewald, A. E. Carter, D. J. Sall and J. A. Monn, "Conformational Preference for the Binding of Bi-Aryl Substrates and Inhibitors to the Active Site of Phenylethanolamine N-Methyltransferase (PNMT)," J. Med. Chem., 31, 60–65 (1988).
  67. D. J. Sall and G. L. Grunewald, "Inhibition of Phenylethanolamine N-Methyltransferase (PNMT) by Aromatic Hydroxy-substituted 1,2,3,4-Tetrahydroisoquinolines: Further Studies on the Hydrophilic Pocket of the Aromatic Ring Binding Region of the Active Site," J. Med. Chem., 30, 2208–2216 (1987).
  68. G. L. Grunewald, K. M. Markovich and D. J. Sall, "Binding Orientation of Amphetamine and Norfenfluramine Analogues in the Benzonorbornene and Benzobicyclo[3.2.1]octane Ring Systems at the Active Site of Phenylethanolamine N-Methyltransferase (PNMT)," J. Med. Chem., 30, 2191–2208 (1987).
  69. G. L. Grunewald, Q. Ye and F. Takusagawa, "Structures of Two Isomeric Phenylethanolamine Analogs Containing the Benzobicyclo[3.2.1]octane Skeleton," Acta Crystallogr., Sect. C: Cryst. Struct. Commun., C43, 2418–2420 (1987).
  70. T. M. Creese, G. L. Grunewald and M. W. Creese, "The Energy Well Connection Graph: A Use of Curvilinear Coordinates to Achieve Dimension Reduction for Graph Representation of Molecular Conformation Energy Data," Theor. Chim. Acta, 71, 75–88 (1987).
  71. G. L. Grunewald, D. J. Sall and J. A. Monn, "A Computer Graphics Model of the Active Site of Phenylethanolamine N-Methyltransferase and its Use in the Design of Selective Inhibitors," in "QSAR in Drug Design and Toxicology: Proceedings of the 6th European Symposium on Quantitative Structure-Activity Relationships," edited by J.-B. Hadzi and Borka Jerman-Blazic (Elsevier, Amsterdam), 1987, pp. 118–120; [Pharmacochem. Libr., 10, 118–120 (1987)].
  72. G. L. Grunewald, H. Arrington, W. J. Bartlett, T. J. Reitz and D. J. Sall, "Binding Requirements of Phenolic Phenylethylamines in the Benzonorbornene Skeleton at the Active Site of Phenylethanolamine N-Methyltransferase (PNMT)," J. Med. Chem., 29, 1972–1982 (1986).
  73. G. L. Grunewald and M. W. Creese, "Conformational Analysis of Nisoxetine and Fluoxetine, Selective Inhibitors of Norepinephrine and Serotonin Reuptake. Are Conformational Differences an Explanation of Neurotransmitter Selectivity?," Drug Design Delivery, 1, 23–37 (1986).
  74. N. Y. Liang, A. Chandra, R. E. Tessel, G. L. Grunewald and R. T. Borchardt, "Inhibitors of Phenylethanolamine N-Methyltransferase: Effects on Brain Catecholamine Content and Blood Pressure in DOCA-Salt Hypertensive Rats," Res. Commun. Chem. Pathol. Pharmacol., 46, 319–329 (1984).
  75. G. L. Grunewald, M. A. Pleiss, C. L. Gatchell, R. Pazhenchevsky, and M. F. Rafferty, "Gas Chromatographic Quantitation of Underivatized Amines in the Determination of Their Octanol-0.1 N NaOH Partition Coefficients by the Shake-Flask Method," J. Chromatogr., 292, 319–331 (1984).
  76. W. J. Brouillette and G. L. Grunewald, "Synthesis and Anticonvulsant Activity of Some Substituted Lactams and Amides," J. Med. Chem., 27, 202–206 (1984).
  77. M. A. Pleiss and G. L. Grunewald, "An Extension of the f-Fragment Method for the Calculation of Hydrophobic Constants (log P) of Conformationally Defined Systems," J. Med. Chem., 26, 1760–1764 (1983).
  78. T. J. Reitz and G. L. Grunewald, "Carbon-13 Nuclear Magnetic Resonance Examination of Benzonorbornene Derivatives. Assignment of Site of Aromatic Ring Substitution in Benzonorbornen-2-ones," Org. Magn. Reson., 21, 596–601 (1983).
  79. G. L. Grunewald, V. M. Paradkar, B. Pazhenchevsky, M. A. Pleiss, D. J. Sall, W. L. Seibel and T. J. Reitz, "Synthesis of Conformationally-Defined Analogues of Norfenfluramine. A Highly Stereospecific Synthesis of Amines from Alcohols in the Benzobicyclo[2.2.1]heptene System," J. Org. Chem., 48, 2321–2327 (1983).
  80. M. W. Creese and G. L. Grunewald, "Conformational Energies of Fenfluramine: Graphical Representation of Energy as a Function of Four Conformational Variables," J. Amer. Chem. Soc., 105, 2463–2469 (1983).
  81. T. J. Reitz, G. L. Grunewald, C. H. Park and B. K. Lee, "6-Nitrobenzonorbornen-2-one," Cryst. Struct. Commun., 11, 1659–1662 (1982).
  82. N. Y. Liang, R. E. Tessel, G. L. Grunewald and R. T. Borchardt, "Inhibitors of Phenylethanolamine N-Methyltransferase. 2. Comparison of Nonaromatic Analogues of Phenylethanolamines, 7,8-Dichloro-1,2,3,4-tetrahydroisoquinoline (SKF-64139) and 2,3-Dichloro-α-methylbenzylamine: Effects on Rat Brain and Adrenal Catecholamine Content and Blood Pressure," J. Pharmacol. Exp. Ther., 223, 382–387 (1982).
  83. N. Y. Liang, R. E. Tessel, G. L. Grunewald and R. T. Borchardt, "Inhibitors of Phenylethanolamine N-Methyltransferase. 1. Effects of 2-Cyclooctyl-2-Hydroxyethylamine on Rat Brain and Adrenal Catecholamine Content and Blood Pressure," J. Pharmacol. Exp. Ther., 223, 375–381 (1982).
  84. N. Y. Liang, R. T. Borchardt, J. C. Choi, R. E. Tessel and G. L. Grunewald, "Effects of Phenylethanolamine N-Methyltransferase Inhibitors on Rat Brain Catecholamine Levels and Body Temperature," Res. Commun. Chem. Pathol. Pharmacol., 37, 445–452 (1982).
  85. M. F. Rafferty, R. T. Borchardt and G. L. Grunewald, "Directional Probes of the Hydrophobic Component of the Aromatic Ring Binding Site of Norepinephrine N-Methyltransferase," J. Med. Chem., 25, 1204–1208 (1982).
  86. M. F. Rafferty, P. Krass, R. T. Borchardt and G. L. Grunewald, "2-(Aminomethyl)-trans-2-decalols as Inhibitors of Norepinephrine N-Methyltransferase. Importance of the Aromatic Ring in Adrenergic Amines. 8.," J. Med. Chem., 25, 1250–1252 (1982).
  87. G. L. Grunewald, J. A. Monn, M. F. Rafferty, R. T. Borchardt and P. Krass, "Probes of the Active Site of Norepinephrine N-Methyltransferase: The Effect of Hydrophobic and Hydrophilic Interactions on Side Chain Binding of Amphetamine and α-Methylbenzylamine," J. Med. Chem., 25, 1248–1250 (1982).
  88. M. F. Rafferty, D. S. Wilson, J. A. Monn, P. Krass, R. T. Borchardt and G. L. Grunewald, "Comparison of the Stereoselectivity of Norepinephrine N-Methyltransferase for Aromatic versus Non-aromatic Substrates and Inhibitors. The Importance of the Aromatic Ring in Adrenergic Amines. 7.," J. Med. Chem., 25, 1198–1204 (1982).
  89. G. L. Grunewald, M. A. Pleiss and M. F. Rafferty, "Conformational Preferences of Dopamine Analogues for Inhibition of Norepinephrine N-Methyltransferase. Conformationally Defined Adrenergic Agents. 7.," Life Sciences, 31, 993–1000 (1982).
  90. M. F. Rafferty and G. L. Grunewald, "The Remarkable Substrate Activity for Phenylethanolamine N-Methyltransferase of Some Conformationally-Defined Phenylethylamines Lacking a Side Chain Hydroxyl Group. Conformationally-Defined Adrenergic Agents. 6.," Mol. Pharmacol., 22, 127–132 (1982).
  91. G. L. Grunewald and M. F. Rafferty, "Conformational Aspects of Binding of Substrates and Inhibitors of Phenylethanolamine N-Methyltransferase (PNMT)," in "The Biochemistry of S-Adenosylmethionine and Related Compounds," edited by R. T. Borchardt, C. R. Creveling and E. Usdin (Macmillan and Company, London), 1982, pp. 453–456.
  92. N. Liang, R. E. Tessel, R. T. Borchardt and G. L. Grunewald, "The Use of Phenylethanolamine N-Methyltransferase Inhibitors in Elucidating the Role of Brain Epinephrine in the Control of Cardiovascular Function," in "The Biochemistry of S-Adenosylmethionine and Related Compounds," edited by R. T. Borchardt, C. R. Creveling and E. Usdin (Macmillan and Company, London), 1982, pp. 457–460.
  93. C. B. Brouillette, W. J. Brouillette, G. L. Grunewald, C. L. Cole, J. R. Ruble and B. K. Lee, "1-Ethoxycarbonyl-3-hydroxy-3-phenyl-2-piperidone," Cryst. Struct. Commun., 10, 1239–1243 (1981).
  94. G. L. Grunewald, R. T. Borchardt, M. F. Rafferty and P. Krass, "Conformational Preferences of Amphetamine Analogues for Inhibition of Phenylethanolamine N-Methyltransferase. Conformationally Defined Adrenergic Agents. 5.," Mol. Pharmacol., 20, 377–381 (1981).
  95. G. L. Grunewald and M. W. Creese, "Fenfluramine, (±)-N-Ethyl-m-(trifluoromethyl)amphetamine Hydrochloride," Acta Crystallogr., B37, 1790–1793 (1981).
  96. G. L. Grunewald and M. F. Rafferty, "Stereochemical Aspects of Binding of Aromatic and Non-aromatic Substrates and Inhibitors to Phenylethanolamine N-Methyltransferase," in "Function and Regulation of Monoamine Enzymes: Basic and Clinical Aspects." edited by E. Usdin, N. Weiner and M. B. H. Youdim (Macmillan and Company, New York), 1981, pp. 691–699.
  97. D. P. Davis, R. T. Borchardt and G. L. Grunewald, "Non-aromatic Analogues of Phenylethanolamine as Inhibitors of Phenylethanolamine N-Methyltransferase: the Role of π-Electronic and Steric Interactions. Importance of the Aromatic Ring in Adrenergic Amines. 6.," J. Med. Chem., 24, 12–16 (1981).
  98. W. C. Vincek, C. S. Aldrich, R. T. Borchardt and G. L. Grunewald, "Non-aromatic Analogues of Phenylethanolamine as Inhibitors of Phenylethanolamine N-Methyltransferase: the Role of Hydrophobic and Steric Interactions. Importance of the Aromatic Ring in Adrenergic Amines. 5.," J. Med. Chem., 24, 7–12 (1981).
  99. G. L. Grunewald, S. H. Kuttab, M. A. Pleiss, J. B. Mangold and P. Soine, "Conformationally Defined Aromatic Amino Acids. Synthesis and Stereochemistry of 2-endo- and exo-Amino-1,2,3,4-tetrahydro-1,4-ethanonapthalene-2-carboxylic Acids (2-endo- and exo-Aminobenzobicyclo[2.2.2]-octene-2-carboxylic Acids)," J. Med. Chem., 23, 754–758 (1980).
  100. G. L. Grunewald, T. J. Reitz, A. Hallett, C. O. Rutledge, S. Vollmer, J. M. Archuleta III and J. A. Ruth, "Pronounced Pharmacological Differences Arising from Minor Structural Changes in Conformationally Defined Amphetamine Analogues. Comparative Evaluation of endo- and exo-2-Amino- and 2-Methylaminobenzobicyclo[2.2.1]heptene and Benzobicyclo[2.2.2]octene Analogues. Conformationally Defined Adrenergic Agents. 4.," J. Med. Chem., 23, 614–620 (1980).
  101. G. L. Grunewald, W. J. Brouillette and J. A. Finney, "Synthesis of α-Hydroxyamides via the Cyanosilylation of Aromatic Ketones," Tetrahedron Lett., 21, 1219–1220 (1980).
  102. G. L. Grunewald, M. W. Creese and D. E. Walters, "Application of CNDO/2 Calculations and X-ray Crystallographic Analysis to the Design of Conformationally-Defined Analogs of Methamphetamine," in "Computer-Assisted Drug Design," R. C. Olson and R. E. Christoffersen, eds., American Chemical Society Symposium Series: American Chemical Society, Washington, D. C., Vol. 112, Ch. 21, 439–487 (1979).
  103. G. L. Grunewald, W. C. Vincek, D. P. Davis and R. T. Borchardt, "Some New Inhibitors of Epinephrine Biosynthesis. Importance of the Aromatic Ring in Adrenergic Amines. 4.," in "Catecholamines: Basic and Clinical Frontiers," edited by E. Usdin, I. J. Kopin and J. Barchas (Pergamon Press, New York), 1979, pp. 189–191.
  104. W. J. Brouillette, E. E. Smissman and G. L. Grunewald, "N-Acylcarbamates as Intermediates in Synthetic Approaches to a Bicyclic Trimethylene-bridged 2,4-Oxazolidinedione and Hydantoin," J. Org. Chem., 44, 839–843 (1979).
  105. G. L. Grunewald, T. J. Reitz, J. A. Ruth, S. Vollmer, L. E. Eiden and C. O. Rutledge, "The Inhibition of Neuronal Uptake of 3H-Biogenic Amines into Rat Cerebral Cortex by Partially and Fully Saturated Derivatives of Imipramine and Desipramine. Importance of the Aromatic Ring in Adrenergic Amines. 3.," Biochem. Pharmacol., 28, 417–421 (1979).
  106. V. D. Warner, D. M. Lynch, K. H. Kim and G. L. Grunewald, "The Quantitative Structure-Activity Relationships for Biguanides, Carbamimidates, and Bisbiguanides as Inhibitors of Streptococcus mutans No. 6715," J. Med. Chem., 22, 359–366 (1979).
  107. G. L. Grunewald, D. E. Walters and T. R. Kroboth, "Synthesis of Bridgehead Hydroxyl-Substituted Benzobicyclo[3.2.1]octenes and -octadienes via an Acyloin Rearrangement in the Benzobicyclo[2.2.2]octene Ring System," J. Org. Chem., 43, 3478–3481 (1978).
  108. G. L. Grunewald and D. P. Davis, "A New Convenient Synthesis of Bridgehead Substituted Norbornenes," J. Org. Chem., 43, 3074–3076 (1978).
  109. G. L. Grunewald, D. E. Walters, D. L. Flynn, S. D. Atwood, M. W. Creese, B. A. Frenz and J. M. Troup, "(±)-2-exo- and endo-Methylamino-1,2,3,4-tetrahydro-1,4-ethanonapthalene Hydrochloride," Acta Crystallogr., B34, 3462–3465 (1978).
  110. G. L. Grunewald and W. J. Brouillette, "An Ethoxycarbonyl Migration from an Amide Nitrogen to Oxygen," J. Org. Chem., 43, 1839–1841 (1978).
  111. D. E. Walters, G. L. Grunewald, M. Staples, J. Rodgers, J. R. Ruble and B. Lee, "(±)-9-exo-Amino-5,6,7,8-tetrahydro-5,8-methano-9H-benzocyclohepten-8-ol Hydrochloride," Acta Crystallogr., B34, 947–949 (1978).
  112. J. A. Ruth, G. L. Grunewald and C. O. Rutledge, "Conformationally Defined Adrenergic Agents. III. Importance of Compartmentation in the Release of Norepinephrine from Rat Atria by endo- and exo-2-Methylaminobenzobicyclo[2.2.2]octene, Conformationally Defined Analogs of Methamphetamine," J. Pharmacol. Exp. Ther., 204, 615–624 (1978).
  113. R. M. Bartholow, L. E. Eiden, J. A. Ruth, G. L. Grunewald, J. Siebert and C. O. Rutledge, "Conformationally Defined Adrenergic Agents. II. The Effect of endo- and exo-2-Aminobenzobicyclo-[2.2.2]octene, Conformationally Defined Amphetamine Analogs, on the Uptake and Release of Central Catecholamines," J. Pharmacol. Exp. Ther. 202, 532–543 (1977).
  114. R. T. Borchardt , W. C. Vincek and G. L . Grunewald, "A Liquid Chromatographic Assay for Phenylethanolamine N-Methyltransferase," Anal. Biochem., 82, 149–157 (1977).
  115. V. D. Warner, J. D. Musto, J. N. Sane, K. H. Kim and G. L. Grunewald, "Quantitative Structure-Activity Relationships for 5-Substituted-8-Hydroxyquinolines as Inhibitors of Dental Plaque," J. Med. Chem., 20, 92–96 (1977).
  116. K. H. Kim and G. L. Grunewald, "A Rapid, Convenient, High Yield Procedure for the Regeneration of 2,3-Dichloro-5,6-dicyanobenzoquinone (DDQ) from the Corresponding Hydroquinone (DDHQ)," Org. Prep. Proced. Int., 8, 141–143 (1976).
  117. G. L. Grunewald, J. M. Grindel, P. N. Patil and K. N. Salman, "Importance of the Aromatic Ring in Adrenergic Amines. 2. Synthesis and Adrenergic Activity of Some Non-aromatic Six- and Eight-membered Ring Analogs of β-Phenylethanolamine," J. Med. Chem., 19, 10–16 (1976).
  118. G. L. Grunewald, J. A. Ruth, T. R. Kroboth, B. V. Kamdar, P. N. Patil and K. N. Salman, "Conformationally Defined Adrenergic Agents. I. Potentiation of Norepinephrine in Rat Vas Deferens by endo- and exo-2-Aminobenzobicyclo[2.2.2]octene, Conformationally Defined Analogs of Amphetamine," J. Pharm. Sci., 65, 920–925 (1976).
  119. G. L. Grunewald and J. M. Grindel, "Synthesis of Carbomethoxycyclooctatetraene," Org. Photochem. Syn., 2, 20–22 (1976).
  120. G. L. Grunewald, J. M. Grindel, W. C. Vincek and R. T. Borchardt, "Importance of the Aromatic Ring in Adrenergic Amines. Nonaromatic Analogs of Phenylethanolamine as Substrates for Phenylethanolamine N-Methyltransferase," Mol. Pharmacol., 11, 694–699 (1975).
  121. G. L. Grunewald, I. M. Uwaydah, R. E. Christoffersen and D. Spangler, "ab initio and Semi-Empirical Molecular Orbital Calculations on 1,6-Methano[10]annulene," Tetrahedron Lett., 933–936 (1975).
  122. G. L. Grunewald and A. M. Warner, "Medicinal Chemistry of [10]-Annulenes and Related Compounds. 2. N-(2-Chloroethyl) Derivatives of 11-Azatricyclo[4.4.1.01,6]undecane, 11-Azatricyclo[4.4.1.01,6]undeca-3,8-diene, and 11-Azabicyclo[4.4.1]undeca-1,3,5,7,9-pentaene," J. Med.. Chem., 15, 1192–1194 (1972).
  123. G. L. Grunewald, A. M. Warner, S. J. Hays, R. H. Bussell and M. K. Seals, "Medicinal Chemistry of [10]Annulenes and Related Compounds. 1. 11-Azatricyclo[4.4.1.01,6]undecane, 11-Azatricyclo-[4.4.1.01,6]undeca-3,8-diene, and 11-Azabicyclo[4.4.1]undeca-1,3,5,7,9-pentaene as Antiviral Agents," J. Med. Chem., 15, 747–750 (1972).

From Graduate Research at the University of Wisconsin

  1. H. E. Zimmerman, R. W. Binkley, R. S. Givens, G. L. Grunewald and M. A. Sherwin, "The Barrelene to Semibullvalene Transformation. Correlation of Excited-State Potential Energy Surfaces with Reactivity. Mechanistic and Exploratory Organic Photochemistry. XLIV," J. Amer. Chem. Soc., 91, 3316–3323 (1969).
  2. H. E. Zimmerman, G. L. Grunewald, R. M. Paufler and M. A. Sherwin, "Synthesis and Physical Properties of Barrelene, A Unique Mobius-like Molecule," J. Amer. Chem. Soc., 91, 2330–2338 (1969).
  3. H. E. Zimmerman, G. L. Grunewald and R. M. Paufler, "α–Pyrone," Org. Syn., 46, 101–104 (1966).
  4. H. E. Zimmerman and G. L. Grunewald, "The Chemistry of Barrelene. III. A Unique Photoisomerization to Semibullvalene," J. Amer. Chem. Soc., 88, 183–184 (1966).
  5. H. E. Zimmerman and G. L. Grunewald, "The Chemistry of Barrelene. II. A Remarkable Transformation to Naphthalene Derivatives," J. Amer. Chem. Soc., 86, 1434–1436 (1964).

From Undergraduate Research at Washington State University

  1. A. R. Martin, A. P. Parulkar, D. J. Gusseck, L. J. Anderson, G. L. Grunewald and A. I. White, "Substituted Tetralins I: Synthesis and Analgesic Activities of Some 2-Aminotetralins," J. Pharm. Sci., 58, 340–347 (1969).