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. We continue to pursue the discovery of novel anticonvulsants with new modes of action.
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.
Since the 1980s, several studies have shown that SRIF levels are reduced in the hippocampus and brain cortex in Alzheimer’s disease (AD) patients. Research has also shown that the enzyme neprilysin, an Aβ-peptidase, regulates the steady state levels of Aβ1-42 and Aβ1-40. Furthermore, SRIF has been shown to enhance neprilysin activity. With reduced levels of SRIF, neprilysin activity declines , leading to higher levels of Aβ and toxicity. In collaboration with Drs. Ken Witt and Karin Sandoval, we have reported that acute administration of the sst4 agonist NNC-26-9100 increases activity of neprilysin, leading to lower levels of Aβ and the trimeric Aβ oligomer within extracellular and intracellular fractions. Thus, sst4 agonists may have potential benefit in the treatment of AD. Our studies are continuing on the development of highly selective sst4 agonists.
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.
Crider, A.M.; Witt, K.A. Somatostatin sst4 Ligands: Chemistry and Pharmacology. Mini-Reviews in Med. Chem. 2007, 7, 213-220.
Li, J.; Bourne, S.; De Villiers, M.; Crider, A.; Caira, M. Polymorphism of the Antitubercular Isoxyl. Crystal Growth and Design 2011, 11, 4950-4957.
Wang, X.; Mealer, D.; Rodgers, L.; Sandoval, K.; Witt, K.A.; Stidsen, C.E.; Ankersen, M.; Crider, A.M. 2-Thiohydantoins as Somatostatin Subtype 4 Receptor Ligands. Lett. Drug Des. Dis. 2012, 9, 655-662.
Liu, Z.; Crider, A.M.; Ansbro, D.; Hayes, C.; Kontoyianni, M. A Structure-Based Approach to Understanding Somatostatin Receptor-4 Agonism (sst4). J. Chem. Inf. Model. 2012, 52, 171-186.
Sandoval, K.E.; Farr, S.A.; Banks, W.A.; Crider, A.M.; Morley, J.E. Somatostatin receptor subtype 4- agonist NNC-26-9100 decreases extracellular Abeta 1-42 trimers. Eur. J. Pharmacol. 2012, 683, 116-124.
Sandoval, K.E.; Farr, S.A.; Banks, W.A.; Crider, A.M.; Morley, J.E.; Witt, K.A. Somatostatin receptor subtype 4 agonist NNC 26-9100 mitigates the effect of soluble Aβ42 oligomers via a metalloproteinase. Brain Research, 2013, 1520, 145-156.
El Sayed, K.A.; Foudah, A.I.; Mayer, A.M.S.; Crider, A.M.; Song, D. Synthesis, microbial transformation, and pharmacological evaluation of 4,5-dihydronaphtho[2,1-b]furan-2-ones and related analogues. Med. Chem. Commun. 2013, 4, 1231-1235.