The structure of an antihistamine: cyproheptadine hydrochloride sesquihydrate

Birknes, Bjørn

doi:10.1107/s0567740877004476

Cited by 15 publications

(12 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It can be seen that the chair 1 conformation ofcyproheptadine has the lowest energy. This chair conformation is also found in the crystal structure [13]. The energy difference between the two chair conformations is only 0.6 kcal/mol.…”

Section: Flexibility Of Cyproheptadinementioning

confidence: 61%

“…Chair 1, which is similar to the crystal structure [13], has an energy 0.6 kcal/mol lower than chair 2 ( Table 1). A similar result was found by Sadek et al [10], using the semiempirical method AM 1 (1.1 kcal/mol difference; protonated species; N-Methyl equatorial).…”

Section: Flexibility Of Cyproheptadinementioning

confidence: 85%

“…Ring I Ring n Ring I Ring n ~x4 x2~xl Me bridge Structural Database [13,14], while phenindamine was built with the modeling package Chem-X* using crystal structure fragments.…”

mentioning

confidence: 99%

See 2 more Smart Citations

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Drooge

Kelder

Timmerman

1991

J Computer-Aided Mol Des

View full text Add to dashboard Cite

The active conformation of several histamine H1-antagonists is investigated. As a template molecule we used the antagonist cyproheptadine, which consists of a piperidylene ring connected to a tricyclic system. The piperidylene moiety is shown to be flexible. The global minimum is a chair conformation but, additionally, a second chair and various boat conformations have to be considered, as their energies are less than 5 kcal/mol above the energy of the global minimum. Two semi-rigid histamine H1-antagonists, phenindamine and triprolidine, were fitted onto the various conformations of cyproheptadine in order to derive the pharmacologically active conformation of cyproheptadine. At the same time, the active conformation of both phenindamine and triprolidine was derived. It is demonstrated that, within the receptor-bound conformation of cyproheptadine, the piperidylene ring most probably exists in a boat form.

show abstract

Section: Flexibility Of Cyproheptadinementioning

confidence: 61%

Section: Flexibility Of Cyproheptadinementioning

confidence: 85%

See 1 more Smart Citation

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Drooge

Kelder

Timmerman

1991

J Computer-Aided Mol Des

View full text Add to dashboard Cite

show abstract

“…This extended study included the compounds of which the crystal structures are reported here: seven of the older types of H~ antagonist: methapyrilene (13) (Clark & Palenik, 1972), Z isomer of triprolidine (Pepinsky, Rathlev & Turley, 1959) and triprolidine (14) (James & Williams, 1974a) and (15), (R)-and (S)-chloropheniramine (16) and (17) (James & Williams, 1974b), diphenylpyraline (18) (Precigoux, Barrans, Busetta & Marsau, 1975), clemastine (19) (Ebnother & Weber, 1976), and cyproheptadine (20) (Birknes, 1977); five thiadiazole-l-oxide derivatives compounds, (21)-(25), that had been synthesized and screened for H~ antagonist activity; the isocytosines (26), (27) and (28). This extended study included the compounds of which the crystal structures are reported here: seven of the older types of H~ antagonist: methapyrilene (13) (Clark & Palenik, 1972), Z isomer of triprolidine (Pepinsky, Rathlev & Turley, 1959) and triprolidine (14) (James & Williams, 1974a) and (15), (R)-and (S)-chloropheniramine (16) and (17) (James & Williams, 1974b), diphenylpyraline (18) (Precigoux, Barrans, Busetta & Marsau, 1975), clemastine (19) (Ebnother & Weber, 1976), and cyproheptadine (20) (Birknes, 1977); five thiadiazole-l-oxide derivatives compounds, (21)-(25), that had been synthesized and screened for H~ antagonist activity; the isocytosines (26), (27) and (28).…”

Section: Molecular-modelling Studies On H~ Histamine Antagonistsmentioning

confidence: 99%

“…14. A molecule of cyproheptadine in the conformation found in the crystal (Birknes, 1977) showing the coordinate system used to define the N...N vector and indicating its direction. 14. A molecule of cyproheptadine in the conformation found in the crystal (Birknes, 1977) showing the coordinate system used to define the N...N vector and indicating its direction.…”

Section: Conformational Analysismentioning

confidence: 99%

Structures of histamine H₁-receptor antagonists derived from the cimetidine group of histamine H₂-receptor antagonists

Bannister

Burns²,

Prout³

et al. 1994

Acta Crystallogr Sect B

View full text Add to dashboard Cite

The crystal and molecular structures of ten compounds with strong structural resemblances to the cimetidine group of histamine H2-receptor antagonists, but exhibiting selective H1-receptor antagonist activity, (1)-(7), or H1 and H2 activity (8)-(10), have been determined: (1) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-5- (6-methyl-3-pyridylmethyl)-4-pyrimidone trihydrobromide (temalastine), C21H27BrN5O3+.3Br-, M(r) = 685.09, triclinic, P1, a = 6.314 (2), b = 11.192 (2), c = 19.441 (5) A, alpha = 102.47 (2), beta = 92.77 (2), gamma = 103.28 (2) degrees, V = 1298.51 A3, Z = 2, Dx = 1.75 g cm-3, mu = 61.6 cm-1, F(000) = 672, R = 2.93% for 3208 independent reflexions. (2) 2-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4-pyrimidone, C14H19BrN4O2, M(r) = 355.23, monoclinic, I2/a, a = 16.359 (3), b = 10.469 (6), c = 18.339 (4) A, beta = 90.90 (2) degrees, V = 3140.49 A3, Z = 8, Dx = 1.503 g cm-3, mu = 26.0 cm-1, F(000) = 1176, R = 4.2% for 1872 independent reflexions. (3) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- amino-1,2,5-thiadiazole-1-oxide, C12H16BrN5OS, M(r) = 358.26, triclinic, P1, a = 14.295 (2), b = 12.447 (2), c = 9.917 (2) A, alpha = 95.77 (2), beta = 113.86 (2), gamma = 106.91 (1) degrees, V = 1495.18 A3, Z = 4, Dx = 1.59 g cm-3, mu = 50.96 cm-1, F(000) = 728, R = 5.98% for 5674 independent reflexions. (4) 3-[4-(5-Bromo-3-methyl-2-pyridyl)butylamino]-4- benzylamino-1,2,5-thiadiazole-1-oxide, C19H22BrN5OS, M(r) = 448.38, monoclinic, P2(1)/c, a = 36.293 (7), b = 4.826 (2), c = 11.528 (3) A, beta = 96.91 (2) degrees, V = 2004.27 A3, Z = 4, Dx = 1.49 g cm-3, mu = 39.2 cm-1, F(000) = 920, R = 12.1% for 1945 independent reflexions. (5) 2-[3-(N-Benzyl-N-2- pyridylamino)propylamino]-4-pyrimidone, C19H21N5O, M(r) = 335.4, orthorhombic, Pbna, a = 7.082 (1), b = 19.889 (3), c = 24.899 (3) A, V = 3507.16 A3, Z = 8, Dx = 1.27 g cm-3, mu = 6.24 cm-1, F(000) = 1424, R = 4.05% from 2470 independent reflexions. (6) 3-[3-(N-4-Fluorobenzyl-N-2- pyridylamino)propylamino]-4-ethylamino-1,2,5-thiadiazole-1-oxide, C19H23FN6OS, M(r) = 402.5, monoclinic, P2(1)/n, a = 6.686 (2), b = 14.717 (3), c = 20.850 (5) A, beta = 97.83 (2) degrees, V = 2032.47 A3, Z = 4, Dx = 1.32 g cm-3, mu = 16.41 cm-1, F(000) = 848, R = 8.5% from 2484 independent reflexions. (7) 5-(6-Methyl-3-pyridylmethyl)-2-[3-(5,6,7,8-tetrahydro-8- quinolyl)propylamino]-4-pyrimidone, C23H29N5O2, M(r) = 407.5, monoclinic, P2(1)/c, a = 14.966 (2), b = 16.075 (2), c = 9.1608 (9) A, beta = 99.158 (8) degrees, V = 2175.83 A3, Z = 4, Dx = 1.24 g cm-3, mu = 6.19 cm-1; F(000) = 872, R = 5.3% from 2784 independent reflexions. (8) 2-(4-Phenylbutylamino)-5-(3-pyridyl-methyl)-4-pyrimidone, C20H26N4O3, M(r) = 370.5, monoclinic, P2(1)/c, a = 8.040 (4), b = 21.279 (4), c = 11.404 (2) A, beta = 92.08 (5) degrees, V = 1949.68 A3, Z = 4, Dx = 1.26 g cm-3, mu = 0.93 cm-1, F(000) = 792, R = 4.05% from 3816 independent reflexions.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

Struktur‐Wirkungs‐Beziehungen bei Nefopamhydrochlorid

Klüfers

Petersenn

Röder

1986

Archiv der Pharmazie

View full text Add to dashboard Cite

Die an (+)-Nefopamhydrochlorid (1) durchgefiihrte Rontgenstrukturanalyse (P2,/c, a = 1176,1, b = 773,9, c = 1689,7pm, fi= 97,43", Z = 4) zeigt, da8 der Heterocyclus aus zwei einfachen Strukturelementen zusammengesetzt ist. Fiinf Atome (2,3,4,5 und 6) haben die Anordnung eines Cyclohexan-Fragmentes; zugleich liegen fiinf Atome (2, 1, 10a, 6a und 6) in der Ebene des anellierten Benzolringes. Die beiden Benzolringe stehen, anders als bei den strukturell verwandten Benzodiazepinen, nahezu senkrecht aufeinander. Die fjbereinstimmung der Strukturen von 1 und (-)-Nefopamhydrochlorid-monohydrat wird im Hinblick auf die Starrheit der Konformation diskutiert. Nefopam kann danach als Modellsubstanz f i r Serotonin-Agonisten und -Antagonisten dienen. Als strukturelle Gemeinsamkeit dieser Verbindungen tritt eine aliphatische Aminogruppe auf, die ca. 600 pm vom Zentrum eines Aromaten entfernt etwa in dessen Ringebene liegt oder leicht in diese Position uberfiihrt werden kann. Structure-Activity Relationships of Nefopam HydrochlorideAn X-ray study of (+)-nefopam hydrochloride (1) (P2,/c, a = 1176.1, b = 773.9, c = 1689.7~1~1, = 97.43", Z = 4) shows that the heterocyclic ring has two structurally simple features: Five atoms (2-6) form the C, fragment of a cyclohexane ring, while another five atoms (2, 1,10a, 6a and 6) lie within the plane of the fused benzene ring. The two benzene rings are almost perpendicular to each other, which is remarkably different from the structurally related benzodiazepines. The structure of 1 is practically identical with that found for (-)-nefopam hydrochloride monohydrate, a fact which is discussed under the aspect of conformational rigidity. Nefopam can be taken as a model substance for serotonin agonists and antagonists. As a common structural feature these compounds have an aliphatic amino group which lies (or can be easily placed) at a distance of about 600pm from the center of the aromatic system and nearly within the plane of the system.

show abstract

The structure of an antihistamine: cyproheptadine hydrochloride sesquihydrate

Cited by 15 publications

References 2 publications

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Structures of histamine H₁-receptor antagonists derived from the cimetidine group of histamine H₂-receptor antagonists

Struktur‐Wirkungs‐Beziehungen bei Nefopamhydrochlorid

Contact Info

Product

Resources

About

The structure of an antihistamine: cyproheptadine hydrochloride sesquihydrate

Cited by 15 publications

References 2 publications

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

The histamine H1-receptor antagonist binding site. Part I: Active conformation of cyproheptadine

Structures of histamine H1-receptor antagonists derived from the cimetidine group of histamine H2-receptor antagonists

Struktur‐Wirkungs‐Beziehungen bei Nefopamhydrochlorid

Contact Info

Product

Resources

About

Structures of histamine H₁-receptor antagonists derived from the cimetidine group of histamine H₂-receptor antagonists