The crystal and molecular structure of thiethylperazine, a derivative of phenothiazine

McDowell, J. J. H.

doi:10.1107/s0567740870003424

Cited by 25 publications

(9 citation statements)

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“…In all cases, the side chain is directed toward the convexity of the ring system. Direction of the side chain toward the concavity of the ring system incurred Van der Waal's repulsions [1.9-2.1 kcal/mol (7950-8790 joules/mol)] using the generally accepted angle of t = 1400 between rings A and C (17,18). The global energy minimum in our calculations is zone no.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

Feinberg¹,

Snyder²

1975

Proc. Natl. Acad. Sci. U.S.A.

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The antischizophrenic activity of phenothiazine drugs and their tendency to elicit extrapyramidal symptoms are thought to involve blockade of synaptic dopamine receptors in the brain. Space filling molecular models show how favorable Van der Waal's interactions between the side chain amino of phenothiazines and the 2-substituent on ring A can promote a conformation mimicking dopamine. These Van der Waal's attractive forces can explain (i) the greater potency of drugs with trifluoromethyl rather than chlorine as a 2-substituent; (ii) the enhanced activity of phenothiazines with piperazine instead of alkylamino side chains; (iii) the increased potency associated with hydroxyethylpiperazines as contrasted to piperazine side chains ; (iv) the greater potency of cis rather than trans thioxanthenes; and (v) the crucial location of the ring A substituent at carbon no. 2. Potential energy calculations support the observations with molecular models and suggest an active conformation for the phenothiazines.An abundance of recent research suggests that a major mechanism whereby antischizophrenic phenothiazine drugs exert their therapeutic actions and extrapyramidal side effects involves a blockade of synaptic receptor sites for dopamine in the brain (1, 2). The activity of a dopamine-sensitive adenylate cyclase correlates with dopamine receptor activity (3). Relative potencies of several phenothiazine and related drugs as inhibitors of the dopamine-sensitive adenylate cyclase parallel their antischizophrenic potency (4-6). Earlier we proposed a molecular model wherein dopamine could be superimposed upon a portion of the chlorpromazine molecule (7). While explaining some structure-activity characteristics of phenothiazines, this model did not deal with important features such as the greater potencies of phenothiazines with piperazine rather than alkylamino side chains, nor did it explain the greater potency of trifluoromethyl than of chlorine ring substituents. Moreover, it provided no explanation for the mechanism whereby the A ring substituent caused the side chain to tilt toward the A ring, nor did it explain why the A ring substituent must be located in the number 2 position.In the present study, Corey-Pauling-Koltun molecular models and computer calculations support a model in which phenothiazines assume a conformation that mimics that of dopamine, explaining the role of trifluoromethyl, piperazine, and hydrox-yethvlpiperazine groups as well as the mechanism whereby A ring substituents influence the side chain. MATERIALS AND METHODSMolecular models of promazine, chlorpromazine, triflupromazine, prochlorperazine, trifluoperazine, thiethylperazine, 1899 perphenazine, and fluphenazine were constructed with CoreyPauling-Koltun kits (Ealing Corp.; Cambridge, Mass.). To confirm the apparent influence of Van der Waal's forces on the side chain conformation, we performed potential energy calculations on the following three compounds with differing ring substituents but the same side chain: promazine, chlorpromazine, an...

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Section: Resultsmentioning

confidence: 99%

“…A special connectivity table was prepared for the phenothiazine ring system (16), and its bond lengths and bond angles were obtained from the published crystal structure of thiethylperazine (17). It might have been more natural to use published data on chlorpromazine (18), but these yielded bizarre ring atom placements.…”

Section: Methodsmentioning

confidence: 99%

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

Feinberg¹,

Snyder²

1975

Proc. Natl. Acad. Sci. U.S.A.

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“…These include phenothiazine (Bell, Blount, Briscoe & Freeman, 1968), N-methylphenothiazine (Chu & Van der Helm, 1974), phenothiazine-10-propionic acid (Malmstrom & Cordes, 1972), phenothiazine-10-propionitrile (Malmstrom & Cordes, 1973), chlorpromazine (McDowell, 1969), thiethylperazine (McDowell, 1970), thiazinamium (Marsau & Cam, 1973), promethazine (Marsau & Busetta, 1973), and methoxypromazine (Marsau & Gauthier, 1973). In this work, the crystal structure of N-ethylphenothiazine (I) has been determined with the objective of determining the effect of the N-substituent on the stereochemistry of phenothiazines in order to explain the difference in the chemical reactivity of the different N-substituted phenothiazines (Biehl, 1974).…”

Section: Introductionmentioning

confidence: 99%

The crystal structure of N-ethylphenothiazine

Chu¹,

Helm²

1975

Acta Crystallogr Sect B

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The crystal structure of N-ethylphenothiazine, C~4HI3NS, has been determined by the heavy-atom method. The refinement was carried out by the least-squares method with anisotropic temperature factors based on three-dimensional data to give a final R value of 0.033 for 1258 reflections. The space group is Pna21 with Z= 4, and unit-cell parameters: a = 14-3136 (8), b = 10.8141 (8), and c = 7.6677 (2)/1,.All the hydrogen atoms were located on a difference Fourier synthesis. The best planes of the benzene rings make a dihedral angle of 135"0 °. The average sulfur-carbon bond length is 1-766 (3) A and the C-S-C bond angle is 97.4 (1) °. The packing of the molecules in the crystal is determined by the van der Waals interactions.

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“…Some results of C N D~/~ calculations on perazine and N-piperidinopromazine and their C1 and CF3 derivatives are presented for comparison between themselves and to the promazine, chlorpromazine, and triflupromazine results (d orbitals were included). The calculations for perazines were performed for the structure as found in the crystallographic determination of thiethylperazine [31]. The numbering system is shown in Figure 2.…”

Section: B Quantum Chemical Calculationsmentioning

confidence: 99%

The structure of psychotropic drugs (including theoretical prediction of a new class of effective neuroleptics)

Kaufman

Kerman

2009

Int. J. Quantum Chem.

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A brief introductory review is presented of the etiology of affective disorders, the neuropsychopharmacological modalities used in treating these states, and the mechanisms by which these therapies act. The topological and topographical requisites for effective neuroleptic (antipsychotic) drugs (the major tranquillizers) are outlined. Quantum chemical results. both CNDoi.2 and INDO. are presented for promazine. perazine. and their CI and CF, derivatives. Application of the topographical postulates led us to perform quantum chemical calculations on a series of hitherto unsynthesized and untested compounds. N-piperdinopromazines. We predicted these would he effective neuroleptics. In the interim a compound of this type was synthesized and tested and it is. indeed. a major tranquillizer. The subtle differences in geometrical conformation between tricyclic neuroleptics (which are postsynaptic dopamine blockers) and the closely related tricyclic antidepressants (which inhibit reuptake of norepinephrine and serotonin back into the the presynapse) are indicated.In the area of hallucinogens or psychotomimetic agents. it is emphasized that even though compounds like LSD and mescaline exhibit cross tolerance, they apparently do not act by the same mechanism. Thus the commonalities in structures between these two groups previously invoked by other authors merit reexamina:ion and a sharpening of focus. Quantum chemical results, CNWl.2 and PCILO, are presented for a few of these compounds whose crystal structures have been determined recently. Our interest in these psychotomimetics was twofold; first. because of their intrinsic interest in the hierarchy of psychotropic drugs and second. to gain insight into why many narcotic antagonists are undesirably psychotomimetic.

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The crystal and molecular structure of thiethylperazine, a derivative of phenothiazine

Cited by 25 publications

References 5 publications

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

Phenothiazine drugs: structure-activity relationships explained by a conformation that mimics dopamine.

The crystal structure of N-ethylphenothiazine

The structure of psychotropic drugs (including theoretical prediction of a new class of effective neuroleptics)

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