Conformational analysis of the ergot alkaloids ... - ACS Publications

L. Pierri, I. H. Pitman, I. D. Rae, D. A. Winkler, and P. R. Andrews. J. Med. Chem. , 1982, 25 (8), pp 937–942. DOI: 10.1021/jm00350a010. Publicatio...
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J.Med. Chem. 1982,25,937-942

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Conformational Analysis of the Ergot Alkaloids Ergotamine and Ergotaminine L. Pierri,t I. H. Pitman,? I. D. Rae,$ D. A. Winkler,l and P. R. Andrews*g* School of Pharmaceutics and School of Chemistry, Victorian College of Pharmacy Ltd., Parkville 3052, Australia, and Chemistry Department, Monash University, Clayton 3168, Australia. Received December 28, 1981 Conformationalanalyses by 'H NMR and potential-energycalculations are reported for the ergot alkaloids ergotamine and ergotaminine, both as free bases and as the protonated species. In the neutral forms in CDCl,, two strong intramolecular hydrogen bonds fix the molecules in folded conformations, but the protonated species adopt a more extended conformation, with a single intramolecular hydrogen bond. Of the 24 alternative conformations available to ergotamine, the most likely biologically active species in environments with low dielectric constants,e.g., the presumed ergotamine binding site, is the folded, hydrogen-bonded conformation observed for the neutral molecule in CDC13 solution.

Ergotamine (1) is an ergot alkaloid which can be an

1

2

effective drug for the treatment of migraine if it is introduced into the blood early in a migraine attack.l Problems can arise in ergotamine therapy of migraine because (1) the drug has a relatively slow rate of absorption from the gastrointestinal tract and (2) the drug has a tendency to epimerize to the pharmacologically inactive alkaloid ergotaminine (2). Several studies have been conducted on the mechanism of absorption of 1 and the manner in which this is enhanced by caffeineS2+ The present paper is a study of the alternative conformations accessible to 1 and 2. This information was sought as a basis for the design of prodrugs of 1 that would be more stable with respect to epimerization or of analogues that would be likely to possess similar biological activity. Molecular conformations were investigated using lH NMR and molecular orbital and classical potential-energy calculations.

Experimental Section 'H NMR spectra were recorded on a Bruker HX270 spectrometer a t the National NMR Centre, Canberra. They were measured a t 25 OC using dilute solutions (0.02 M) in CDCl,, with tetramethylsilane as internal standard. Trifluoroacetic acid was added to the solutions for measurementson the protonated forms. Calculations were done on the neutral and protonated forms of 1 and 2. At physiological pH, assuming pK, values of 6.25 (1) and 6.72 (2); the neutral froms would predominate. The molecular geometries were estimated using crystal data for LSD6v7 and aci-p-iodobenzoylaminocyclol,8since crystal structures for 1 and 2 were not available. The calculations were performed with a Cyber 72 computer using the program COMOL.' The program performs classical conformational calculations by pairwise summation of Van der Waal's interactions between nonbonded atoms, together with electrostatic and torsional potentials. The parameterization,which was developed by Giglio on the basis of a series of hydrocarbon and amide structures,1° has been used to study a number of systems of biological interest,l1-l3 The atomic charges, used to calculate the electrostatic potentials, were obtained from a MIND013 molecular orbital calcu'School of Pharmaceutics, Victorian College of Pharmacy Ltd. t Monash University. 5 School of Chemistry, Victorian College of Pharmacy Ltd. 0022-262318211825-0937$01.25/0

lationI4 on the above geometry. The calculations were carried out at fixed values of all bond lengths and bond angles. Preliminary calculations indicated that relaxation of this condition did not affect the qualitative nature of the potential-energy surfaces. Four torsional angles are required to describe the conformations of ergotamine or ergotaminine, and these are defined in Figure 1. Initially, these variables were considered two at at time and approximate potential-energy surfaces were computed for each compound using torsional intervals of 12'. The calculations for each pair were then repeated for alternative values of the other two torsion angles. With both pairs of torsional variables near their minimum-energy values, very little interaction was found between the amide pair and the benzyl pair. A further conformational variable is provided by the D ring, which may assume either a flap up (I) or flap down (11) conformation. In addition, the methyl group on N6 may adopt positions a or p with respect to the proton on C5(defined as p). Calculations were performed for each combination of these alternative D-ring conformations, Le., flap up or flap down, methyl a or methyl 6. Conformationalenergy maps were prepared using a modification of the contouring program KONTOR.'' Ergotamine (1) was prepared from ergotamine tartrate (Boehringer Ingelheim) and recrystallized from acetone-water (9O:lO). Compound 2 was prepared from 1 by refluxing with MeOH and glacial HOAc (0.20%) under a N2 atmosphere for 1 h.

Results and Discussion lH NMR. The chemical shifts and coupling constants for the free bases 1 and 2 in deuteriochloroform are presented in Tables I and 11, along with the splitting pattern for each hydrogen. The assignments were made by consideration of chemical shifts and coupling constants, supported by spin-decoupling experiments, with reference to similar analyses of the spectra of lysergic acid diJ. M. Bradfield, Curr. Ther., 17, 55 (1976). M. A. Zoglio, H. V. Maulding, and J. J. Windheuser, J.Pharm. Sci., 58, 222 (1969). H. V. Maulding and M. A. Zoglio, J. Pharm. Sci., 59, 700 (1970).

J. R. Anderson and I. H. Pitman, J. Pharm. Sci., 69, 832 (iwml.

JTR.-Anderson, G. Drehsen, and I. H. Pitman, J. Pharm. Sci., 70, 651 (1981). R. W. Baker, C. Chothia, P. Pauling, and H. P. Weber, Science, 178,614 (1972). C. Chothia and P. Pauling, Proc. Natl. Acad. Sci. U.S.A., 63, 1063 (1969). A. T. McPhail, G. A. Sim, A. J. Frey, and H. Scott, J. Chem. SOC. B,377 (1966). M. H. J. Koch, Acta Crystallogr., Sect. B, 29, 379 (1973). E. Giglio, Nature (London),222, 339 (1969). M. D'Algani, E. Giglio, and N. V. Pavel, Polymer, 17, 257 (1976). M. L. de Winter, T. Bultsma, and W. T. Nauta, Eur. J. Med. Chem., 12, 137 (1979). G. P. Jones and P. R. Andrews, J. Med. Chem., 23,444 (1980). R. C. Bingham, M. J. S. Dewar, and D. H. Lo, J. Am. Chem. SOC., 97, 1285 (1975). J. A. B. Palmer, Aust. Camp. J.,2, 27 (1970). 0 1982 American Chemical Society

938 Journal of Medicinal Chemistry, 1982, Vol. 25, No. 8

Pierri et al.

Table I. 'H Chemical Shifts and Coupling Constants in Ergotamine (1) H resonances 1 2 401 44 54 6-CH3 70: 74 8ff 9 20-NH 12-14 2'CH, 5' 8' & 11' 9' & 10' 13'a 13'4 15'OH

J, Hz

chem shift, 6 8.137 6.907 2.790 3.322 3.733 2.606 2.958 2.777 3.176 6.342 9.039 7-7.5 1.506 4.687 -3.6 -2.1 3.455 3.263 6.970

H2