Discovery of a novel, structurally unique class of muscarinic agonists

1164

Vol. 60, Nos. 13114, 1997

Abstracts

3 DISCOVERY AGONISTS

OF A NOVEL,

STRUCTURALLY

UNIQUE

CLASS

OF

MUSCARINIC

K.M. Ward, S.T. Hubbard, S.B. Jones, D.M. Nason, M.H. Lee, C. K. Biggers, J. Nowakowski, D. Yohannes, A. Villalobos, R.M. Snider, W.F. White and D.R. Liston. Departinents of Neuroscience and Medicinal Chemistry, Central Research Division, Pfizer Inc, Groton, Conn 06340 USA The discovery of a novel series of potent muscarinic agonists with unique structural features is reported. Compounds with potent binding to M 1 receptors were identified by empirical screening of a large compound library; active compounds were screened further in a functional assay for stimulation of phosphatidylinositol (PI) hydrolysis in CHO cells expressing the human ml receptor. One compound, an amidinoguanidine, showed potent agonist activity. Subsequent synthetic chemistry resulted in a series of very potent muscarinic agonists. Many compounds were discovered which were full agonists at ml receptors expressed in CHO cells, with EDSO’s
4 CONFORMATIONALLY CONSTRAINED ANALOGS OF THE MUSCARINIC SYNTHESIS, RECEPTOR AFFINITY AND ANALGESIC ACTIVITY

AGONIST

METHYLTHIO-TZTP.

P. Sauerberg, P.H. Olesen, H. Thegersen, S. Nielsen, M.J. Sheardown, K. Rimvall, #H.E. Shannon, #J.S. Ward, #C.H. Mitch, #F.P. Bymaster, M.D.B. Swedberg Novo Nordisk A/S, Health Care Discovery, Novo Nordisk Park, 2760 M&v, Denmark and #Lilly Research Laboratories, Eli Lilly and Co., Indianapolis IN 46285 The potent muscarinic receptor agonist 3-(4-methylthio1,2,5-thiadiazol-3-yl)1,2,5,6_tetrahydro1-methylpyridine (methylthio-TZTP) is a relatively flexible molecule. Attempts to predict the active conformation with regard to the angle between the tetmhydropyridine ring and the thiadiazole ring have previously been published (Ward et al. 1992, Periyasamy et al. 1995). The Schulman model suggested the angle to be close to 90” (Ward et al.), whereas the minimum energy conformation predicted the angle to be 180” (Periyasamy et al.). Tricyclic analogs of methylthio-TZTP, with a fixed angle at 1SO”, and a rotation hindered 4-Me-methylthio-TZTP analog, with energy minimum close to 90”, have now been synthesized and tested for muscarinic receptor affinity. A second purpose of synthesizing more rigid analogs of methylthio-TZTP was to improve the analgesic selectivity (Sauerberg et al. 1995). Consequently, the compounds were also tested for analgesic effects in the mouse grid shock test with simultaneous scoring of the side effects tremor and salivation. The data showed that the tricyclic analogs had somewhat lower receptor affinity than methylthio-TZTP, but were equally potent as analgesics. The analgesic/side effect ratios had not been improved. The 4-Me-methylthio-TZTP analog was inactive in both tests. p_p

@$S

4-Me-methylthio-TZTP

Methylthio-TZTP References:

Ward et al. J. Med. Chem.

Life Sci. 1995, 56, 807.

1992,35,4011.

Periyasamy

et al. Brain Research

1995, 693, 118. Sauerberg

et al.