About Us

Michael Crider, Ph.D.

Research: Medicinal Chemistry

Over the course of my academic career, my research has been focused on the discovery of novel compounds with potential therapeutic effects in the central nervous system, prodrugs, and peptidomimetics. During my graduate work at the University of Kentucky, I was involved in the design of compounds with potential long-acting anticonvulsant effects. Our approach involved attaching alkylating groups at various positions on the succinimide ring system in an attempt to produce compounds capable of binding covalently to a receptor site. Although many of these compounds exhibited potent anticonvulsant activity, none had an appreciably long duration of action. In retrospect, the idea of covalently attaching a drug, such as an anticonvulsant, to a receptor site, probably would not lead to a long acting compound. Nevertheless, my graduate work stimulated an interest on the chemistry of five-membered nitrogen heterocycles throughout my academic career.

My interest in dopaminergic ligands stems from my postdoctoral work at Purdue University under the direction of Professor John Cassady. At the time, we were interested in the development of prolactin inhibitors based on the ergoline ring system. Dopamine was known to be an inhibitor of prolactin release and that certain breast tumors were prolactin-dependent. Thus, the discovery of dopaminergic ligands having prolactin inhibiting activity was of potential therapeutic value. After leaving Purdue for my first faculty position at the University of Toledo, I became involved in the synthesis of ergoline fragments having dopaminergic activity. However, the piperidine ring (D-ring) contained in the ergoline ring system was replaced by the five-membered pyrrolidine ring system. This research was pursued in collaboration with Peter Andersen and Mark Scheidelar at Novo Nordisk A/S in Denmark. We discovered that the tricyclic benz[e]indole ring system provided the framework for compounds with potent affinity for the dopamine D3 receptor.

Another major area of research, also in collaboration with Novo Nordisk A/S, in my laboratory over the last 12 years has been in the development of nonpeptide ligands of somatostatin [somatotropin release-inhibiting factor (SRIF)]. Research from a number of laboratories has shown that the b-turn, Phe 7-Trp 8-Lys 9-Thr 10, is necessary for biological activity with residues Trp 8 and Lys 9 being essential. Additional studies have shown that the Phe 6 and Phe 11 residues may help stabilize the bioactive conformation of SRIF. SRIF exerts its biological effects by binding to a family of G-protein-coupled receptors (sst 1-sst 5). Due to its poor bioavailablity and rapid degradation by proteases, the therapeutic utility of SRIF-14 is limited. As a result, the development of peptidomimetics of SRIF is of considerable interest. A broad screening program was initiated with collaborators at Novo Nordisk A/S focusing on a scaffold to which Phe 7, Trp 8, and Lys 9 mimetic were attached. This focused screen led to the discovery of a thiourea (NNC 26-9100) with high affinity (K i = 6 nm) for the subtype 4 somatostatin receptor (sst 4). This was the first report of a nonpeptide exhibiting high binding affinity and selectivity at a cloned human receptor. Subsequent studies from our laboratory have been directed at exploring the structure activity relationships of thioureas and related compounds at ssts. Present studies are directed toward microwave-assisted synthesis of novel scaffolds that contain the key structural fragments which are thought to impart binding affinity for ssts.

Representative Publications

Ho, B.; Venkatarangan, P.M.; Cruse, S.F.; Hinko, C.N.; Andersen, P.H.; Crider, A.M.; Adloo, A.A.; Roane, D.S.; Stables, J.P. Synthesis of 2-Piperidinecarboxylic Acid Derivatives as Potential Anticonvulsants. Eur. J. Med. Chem. 1998, 33, 23-31

Ankersen, M.; Crider, M.; Liu, S.; Ho, B.; Andersen, H.S.; Stidsen, C.E. Discovery of a Novel Nonpeptide Somatostatin Agonist with SST 4 Selectivity. J. Am. Chem. Soc.1998,120, 1368-1373

Liu, S.; Crider, A. M.; Tang, C.; Ho, B.; Ankersen, M.; Stidsen, C. E. Nonpeptide Somatostatin Agonists with sst 4 Selectivity: Synthesis and Structure Activity Relationships of Thioureas. J. Med. Chem. 1998, 41, 4693-4705

Song, X.; Crider, A. M.; Cruse, S. F.; Ghosh, D.; Klein-Stevens, C.; Liang, L.; Scheideler, M. A.; Varming, A. cis-and trans-2,3,3a,4,5,9b-Hexahydro-1H-benz[e]indoles: Synthesis and Evaluation of Dopamine D 2 and D 3 Receptor Binding Affinity. Eur. J. Med. Chem. 1999, 34, 487-503

Crider, A.M.; Liu, S.; Li, T.; Mahajan, S.; Ankersen, M.; Stidsen, C.E. Somatostatin Receptor Subtype 4 (sst 4) Ligands: Synthesis and Evaluation of Indol-3-yl- and 2-Pyridyl-thioureas, Letters in Drug Design and Discovery 2004, 1, 84-87.