COMMUNICATIONS
Table 1. Binding constants in complexes formed between host 2 and various guest molecules without (9 ± 15) and with an alkyl or aryl substitutent a to the
N atom (16 ± 20) as determined by NMR titrations in D2O:MeOD (1:1).
1
[b]
1
[b]
[b,c]
Guest[a]
Ka (1:1) [m
]
DG [kJmol
]
Ddsat
Stoichiom.[d]
adrenaline 9 (R Me)
153 Æ 14%
215 Æ 12%
246 Æ 38%
102 Æ 14%
54 Æ 45%
204 Æ 5%
137 Æ 7%
12.5
13.3
13.6
11.5
9.9
0.17 Æ 10%
0.12 Æ 8%
0.20 Æ 26%
0.41 Æ 11%
0.07 Æ 34%
0.23 Æ 3%
0.36 Æ 6%
no saturation
no saturation
no saturation
no saturation
no saturation
1:1
1:1
1:1
1:1
1:1
1:1
1:1
noradrenaline 10 (R H)
dopamine 11
2-phenylethylamine 12
ethanolamine 13
propranolol 14
13.2
12.1
d-threo-2-amino-1-(4-nitrophenyl)-1,3-propanediol (ANP) 15
a-methyl-4-nitrobenzylamine 16
l-tyrosine methyl ester 17
l-alanine methyl ester 18
d-tryptophan methyl ester 19
d-tryptophan tert-butyl ester 20
weak binding[e]
weak binding
weak binding
weak binding
weak binding
±
±
±
±
±
complex
complex
complex
complex
complex
[a] As hydrochloride salts. [b] Errors [%] are calculated as standard deviations from the nonlinear regression. [c] Bound shift at 100% complexation,
obtained from the curve fitting (selected CH protons). [d] From Job plots and curve-fitting of the titration curves. [e] Maximum observed chemical shifts
1
Dd 0.03; upper limits for Ka are estimated at <10m
.
[1] T. P. Iisma, T. J. Biden, J. Shine,
G Protein-Coupled Receptors,
indicative of p-stacking interactions, which are necessary for
the postulated sandwich-type binding mode of host 2.
Springer, Heidelberg, 1995.
[2] Recent GPCR crystal structures: a) E. Pebay-Peyroula, G. Rummel,
J.-P. Rosenbusch, E. M. Landau, Science 1997, 277, 1676; b) D. Doyle,
J. M. Cabral, R. A. Pfuetzner, A. Kuo, J. M. Gulbis, S. L. Cohen, B. T.
Chait, R. Mackinnon, Science 1998, 280, 69; c) K. Palczewski, T.
Kumasaka, T. Hori, C. A. Behnke, H. Motoshima, B. A. Fox, I.
Le Trong, D. C. Teller, T. Okada, R. O. Stenkamp, M. Yamamoto, M.
Miyano, Science 2000, 289, 739 ± 745.
[3] a) M. I. Rodriguez-Franco, P. San Lorenzo, A. Martinez, P. Navarro,
Tetrahedron 1999, 55, 2763; b) K. Odashima, K. Yagi, K. Tohda, Y.
Umezawa, Bioorg. Med. Chem. Lett. 1999, 9, 2375; c) R. R. Makote,
M. M. Collinson, Chem. Mater. 1998, 10, 2440.
Another interesting feature is the decrease in binding
energy when the phenolic hydroxyl groups are deleted from
the guest structure (11 versus 12). This effect makes 2
selective for catecholamines. Free phenolic OH groups do
not significantly enhance the electron-rich character of a
benzene ring because of their large negative inductive effect.
Hence, the observed decrease in binding energy must be
explained by loss of hydrogen bonds between the catechol
hydroxyl groups and the isophthalamide head group of the
host molecule. A control experiment in DMSO revealed a
large downfield shift of one of the hydroxyl proton signals in
noradrenaline on formation of a complex with 2, and is
another strong indicator for the formation of hydrogen bonds.
The contribution of hydrogen bonds to the catechol hydroxyl
groups can be estimated in the 1:1 mixture of water and
[4] J. A. Gavin, M. E. Garcia, A. J. Benesi, T. E. Mallouk, J. Org. Chem.
1998, 63, 7663 ± 7669.
[5] a) M.-F. Paugam, L. S. Valencia, B. Bogess, B. D. Smith, J. Am. Chem.
Soc. 1994, 116, 11203; b) M.-F. Paugam, J. T. Biens, B. D. Smith, A. J.
Christoffels, F. de Jong, D. N. Reinhoudt, J. Am. Chem. Soc. 1996, 118,
9820 ± 9825; c) M. B. Inoue, E. F. Velazquez, M. Inoue, Q. Fernando, J.
Chem. Soc. Perkin Trans. 2 1997, 2113 ± 2118.
[6] T. Schrader, M. Herm, Chem. Eur. J. 2000, 6, 47 ± 53.
1
methanol to be about 2.1 kJmol , whereas formation of
[7] In the natural b-adrenergic receptor the binding site is formed by a
cyclic array of seven membrane-spanning a-helices which produce a
rather hydophobic surrounding of the adrenaline guest: S. Trumpp-
Kallmeyer, J. Hoflack, A. Bruinvels, M. Hibert, J. Med. Chem. 1992,
35, 3448 ± 3462.
[8] Molecular mechanics calculations: Cerius2, Molecular Simulations
Inc., force-field: Dreiding 2.21. Monte ± Carlo Simulations and
Molecular Dynamics: Macromodel 7.0, Schrödinger Inc., 2000;
1
p stacks with the catechol arene is worth about 1.6 kJmol .
Table 1 demonstrates a remarkable shape selectivity of the
new adrenaline receptor molecule: in general the slim
dopamine skeleton is a favorable binding motif for 2 (9 ±
15). By contrast, the introduction of an additional substituent
a to the ammonium ion, such as in amino acids, leads to weak
binding and higher stoichiometries. Clearly, these guests are
not included in the interior of the new host (16 ± 20). This
situation is in sharp contrast to host 1, which, as a result of its
large cavity, could not distinguish between amino acids and
adrenaline derivatives. All the effects discussed above con-
firm that macrocyclic host 2 recognizes adrenaline derivatives
in mixtures of water and methanol (1:1) by multiple non-
covalent interactions including electrostatic attraction, hydro-
gen bonds, p stacking, and hydrophobic forces.
In summary, we have designed a shape-selective adrenaline
host for dopamine with a binding constant in water which is
three orders of magnitude lower than that of the natural
example (105 m 1). We are currently optimizing the host
structure by implementing elements of much higher rigidity to
achieve an even more effective preorganization and desolva-
tion.
force-field: Amber*.
A 3000-step Monte ± Carlo simulation was
carried out, followed by a molecular dynamics calculation for 10 ps
at 300 K.
[9] a) E. Negishi, A. O. King, N. Okukado, J. Org. Chem. 1977, 42, 1821 ±
1823; b) reviews: Organozinc Reagents (Eds.: P. Knochel, P. Jones),
Oxford University Press, Oxford, UK, 1999, pp. 213 ± 243; Metal-
Catalyzed Cross Coupling Reactions (Eds.: F. Diederich, P. J. Stang),
Wiley-VCH, Weinheim, 1998, pp. 1 ± 47.
[10] a) P. Job, C. R. Hebd. Seances Acad. Sci. 1925, 180, 928; b) M. T.
Blanda, J. H. Horner, M. Newcomb, J. Org. Chem. 1989, 54, 4626.
[11] Since both the NOE interactions between OH and NH protons as well
as the diagonal are negative, we cannot a priori exclude exchange
phenomena. However, no cross-peak was found between water and
the NH proton.
[12] a) H. J. Schneider, R. Kramer, S. Simova, U. Schneider, J. Am. Chem.
Soc. 1988, 110, 6442; b) C. S. Wilcox in Frontiers in Supramolecular
Chemistry (Ed.: H. J. Schneider), VCH, Weinheim, 1991, p. 123.
Received: March 26, 2001 [Z16850]
Angew. Chem. Int. Ed. 2001, 40, No. 17
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