Sten Rämsby

Crystallographic, theoretical and molecular modelling studies on the conformations of the salicylamide, raclopride, a selective dopamine‐D2 antagonist*

The structure of the potent dopamine‐D2 antagonist, raclopride, (S)‐3,5‐dichloro‐N‐[(1‐ethyl‐2‐pyrrolidinyl)methyl]‐6‐methoxysalicylamide (+)‐tartrate, has been determined by X‐ray crystallography. The benzamide moiety of raclopride is planar in accordance with other salicylamides (FLA 797 and eticlopride). The planar conformation is stabilized by two intramolecular hydrogen bonds, i.e. one between the amide hydrogen and the methoxy group and one between the phenol hydrogen and the carbonyl group. The side‐chain of raclopride has an extended conformation in contrast to the solid state conformations of FLA 797 and eticlopride. The side‐chain conformations were studied by rigid rotations followed by MM2PI relaxations of the eight local minima found. Small energy differences (<4ṁ0 kcal mol−1) exist between the various extended and folded conformations. Based on modelling studies with piquindone as template, it is suggested that the salicylamides with N‐ethyl‐2‐pyrrolidinylmethyl side‐chains interact with the dopamine‐D2 receptor in a folded or a half‐folded conformation.

Potential antipsychotic agents. 6. Synthesis and antidopaminergic properties of substituted N-(1-benzyl-4-piperidinyl)salicylamides and related compounds. QSAR based design of more active members

A number of substituted 2-methoxybenzamides, with and without 6-hydroxy groups, with 4-piperidinyl side-chains have been synthesized and evaluated for their antidopaminergic properties. The salicylamides were found to require a lipophilic N-substituent, like a benzyl group, for high affinity for the dopamine D-2 binding site in contrast to salicylamides with 2-pyrrolidinylmethyl side-chains. Furthermore, the influence of the aromatic substituents on the activity in the 2 series, ie 4-piperidinyl and 2-pyrrolidinylmethyl side-chains, was different. This was supported by a Hansch analysis, which could accomodate both phenolic and non-phenolic benzamides with 1-benzyl-4-piperidinyl side-chains. The activity is primarily dictated by electronic features rather than by steric and lipophilic properties. The QSAR equations were validated by the design and synthesis of a new 10-fold more active derivative. The 2 classes of benzamides with different side-chains are suggested to act on different binding sites or on different subtypes of the dopamine D-2 receptor.

Chapter 3. Antipsychotic Agents

Publisher Summary Noninvasive radioimaging techniques have brought new insight into the role of the regional distribution and receptor binding of anti-psychotic agents. Studies of the blood flow in the brains of schizophrenic patients with positron-emitting xenon-133 have revealed an over-activation in the left hemisphere during performance of a spatial line orientation test. Positron emission tomography (PET) scanning with oxygen-15 (half-life 123s) in some schizophrenic patients failed to support the hypothesis of reduced blood flow in frontal cortex. Haloperidol-induced dopamine (DA) receptor supersensitivity in schizophrenics appears to be attenuated by concurrent treatment with lithium. The DA hypothesis of schizophrenia has been reviewed in the light of recent findings. Perioral dyskinesias can be induced acutely in rats by the DA antagonists spiroperidol and sulpiride, and by the selective agonist SKF 38393 but not by the selective agonist LY 141865. Attempts to separate the multitude of effects shown by cyproheptadine have included the introduction of nuclear substituents and replacement of a benzene ring by a pyrrole ring. The conformational flexibility was higher for these new pyrrolo-compounds than for the corresponding cyproheptadine derivatives as evidenced from the rates of racemization of the atropisomers. This chapter discusses the accumulated experience with depot neuroleptics, such as clopenthixol decanoate and pipotiazine palmitate. The anti-hallucinator effect of chlorpromazine correlates with the serum levels of prolactin consistent with the DA hypothesis of schizophrenia. No regional site specificity for limbic areas was found with thioridazine or with clozapine. The chapter discusses the anti-psychotic agents through phenothiazines and related rigid compounds, diphenvlpiperidines and butyrophenones, substituted benzamides, and miscellanious compounds.