5-(4-Chlorophenyl)-4-methyl-3-(1-(2- phenylethyl)piperidin-4-yl)isoxazole:  A Potent, Selective Antagonist at Human Cloned Dopamine D4 Receptors

Rowley, Michael; Broughton, Howard B.; Collins, Ian; Baker, Raymond; Emms, Frances; Marwood, Rosemarie; Patel, Shil; Patel, Smita S.; Ragan, C I; Freedman, Stephen B.; Leeson, Paul D.

doi:10.1021/jm960072u

Cited by 111 publications

(44 citation statements)

References 17 publications

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“…This strategy is under active investigation, for example, by development of specific 0 3 Pugsley et al 1995) and 0 4 ligands (Merchant et al 1996a;Rowley et al 1996). However, there is no evidence for selective binding to 0 2 receptor subtypes for the present generation of novel APDs (see previous discussion in the section on in vitro effects).…”

Section: Effects In Models For Antipsychotic and Eps Activity Limbic mentioning

confidence: 99%

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Arnt

Skarsfeldt

1998

Neuropsychopharmacology

683

443

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The pharmacological properties of the novel antipsychotic drugs (APDs) risperidone, sertindole, olanzapine, quetiapine, ziprasidone, remoxipride, and amperozide are reviewed and compared with haloperidol and clozapine. Focus is made on their receptor profiles, their effects in animal models used for evaluation of antipsychotic activity, and extrapyramidal side effects (EPS). In addition, the contrasting actions of these compounds on animal modelsDuring the last decade there has been a dramatic increase in the efforts to develop novel antipsychotic drugs (APDs) with improved clinical efficacy and fewer or no extrapyramidal side effects (EPS) than the classical APDs such as haloperidol and fluphenazine. These efforts were undoubtedly inspired by the previous development of clozapine, which fulfilled these criteria to a large extent, although having other troublesome side From the Pharmacological Research, H. Lundbeck A/S, Ohiliavej 9, DK-2500, Copenhagen-Valby, Denmark.Address correspondence to: J0rn Arnt, Pharmacological Research, H. Lundbeck A/5, Ottiliavej 9, DK-2500 Copenhagen-Valby, Denmark.Received January 6, 1997; revised June 26, 1997; accepted July 7, 1997. effects (Baldessarini and Frankenburg 1991; Coward 1992;Wagstaff and Bryson 1995;Buchanan 1995; Ashby and Wang 1996).The novel APDs were assigned the popular term "atypical antipsychotic" drugs to differentiate them from the classic or "typical" APDs or neuroleptics. The most widely accepted definition of a neuroleptic is a compound that has antipsychotic activity and induces EPS with high frequency. The definition of "a typicality" was equivocal, however, because the term was often used for drugs before any clinical results were available. For example, the term was applied to a compound that induced little or no catalepsy in rats, and that was effective in another model believed to reflect antipsychotic activity, e.g., inhibition of O-amphetamine (AMPH)-induced hypermotility. A more precise definition is to base it solely on clinical evidence as a wide differentiation between the dosages used to control psychosis and those inducing EPS-or on other aspects of clinical superior-0893-133X/98/$19.00 PI! 50893-133X(97)00112-7 64 J. Arnt and T. Skarsfeldt ity over classic APDs, e.g., efficacy on negative symptoms of schizophrenia or in drug-resistant patients (for recent review, see Kinan and Lieberman 1996). However, because these very different characteristics are difficult to incorporate in a common definition, we suggest that the terminology "atypical" is best avoided. Indeed, as will be discussed, novel APDs show many individual differences.The suggested alternative terminology "novel APO" is also not precise, but it can be defined as a compound that has been shown to inhibit positive symptoms of schizophrenia and has either been recently launched or is in phase II/III clinical development. Their specific profiles can be described more precisely, e.g., EPS-free APO, etc. It is not anticipated that novel APDs will be marketed in the future, unless hav...

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Section: Effects In Models For Antipsychotic and Eps Activity Limbic mentioning

confidence: 99%

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Arnt

Skarsfeldt

1998

Neuropsychopharmacology

683

443

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“…Here we report for the first time that some of the most commonly used dopamine D 4 receptor selective antagonists, L745,870, L741,741 and RBI-257, have nanomolar affinities for the cloned sigma 1 receptor, with the latter two having very high affinities that are within 10-fold of that reported for D 4 receptors (Kulagowski et al, 1996;Rowley et al, 1996;Kula et al, 1999). In contrast, the dopamine D 4 receptor selective agonist PD168,077 (Glase et al, 1997) and antagonist NGD 94-1 (Tallman et al, 1997) have micromolar affinities for the sigma 1 receptor.…”

Section: Discussionmentioning

confidence: 62%

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

Lee

Chen

Schetz

2008

European Journal of Pharmacology

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The ability of sigma 1 receptors to interact with a huge range of drug structural classes coupled with its wide distribution in the body has contributed to it being implicated as a possible therapeutic target for a broad array of disorders ranging from substance abuse to depression to Alzheimer's disease. Surprisingly, the reported affinity values for some sigma 1 receptor ligands vary more than 50-fold. The potential of the sigma 1 receptor as a pharmacotherapeutic target prompted us to develop an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma 1 receptor. In the course of characterizing this system and determining the true affinity values for almost three dozen compounds, it was discovered that some dopamine D 4 receptor selective compounds bind sigma 1 receptors with high affinity. A systematic analysis of haloperidol-like compounds revealed a clear structure-affinity relationship amongst clinically relevant butyrophenones. The antidepressant fluvoxamine, the drug of abuse methamphetamine, and the neurosteroid progesterone were amongst the many ligands whose interactions with sigma 1 receptor were confirmed with our screening assay.

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“…(Kulagowski et al 1996;Rowley et al 1996;Bayfield et al 1996) is not clinically antipsychotic, as mentioned by Dr. Wong (Kramer et al 1996), but such blockade may have another neuropsychopharmacological role, such as possibly alleviating the Parkinsonism of D 2 blockade. It is the purpose of the review to examine this as only one possibility.…”

Section: Are Atypical Neuroleptics Selective For the 5-htmentioning

confidence: 99%

Discussion

1997

Neuropsychopharmacology

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5-(4-Chlorophenyl)-4-methyl-3-(1-(2- phenylethyl)piperidin-4-yl)isoxazole: A Potent, Selective Antagonist at Human Cloned Dopamine D4 Receptors

Cited by 111 publications

References 17 publications

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

Do Novel Antipsychotics Have Similar Pharmacological Characteristics? A Review of the Evidence

An unambiguous assay for the cloned human sigma1 receptor reveals high affinity interactions with dopamine D4 receptor selective compounds and a distinct structure–affinity relationship for butyrophenones

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