H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs.

Article Details

Citation

Kroeze WK, Hufeisen SJ, Popadak BA, Renock SM, Steinberg S, Ernsberger P, Jayathilake K, Meltzer HY, Roth BL

H1-histamine receptor affinity predicts short-term weight gain for typical and atypical antipsychotic drugs.

Neuropsychopharmacology. 2003 Mar;28(3):519-26.

PubMed ID
12629531 [ View in PubMed
]
Abstract

As a result of superior efficacy and overall tolerability, atypical antipsychotic drugs have become the treatment of choice for schizophrenia and related disorders, despite their side effects. Weight gain is a common and potentially serious complication of some antipsychotic drug therapy, and may be accompanied by hyperlipidemia, hypertension and hyperglycemia and, in some extreme cases, diabetic ketoacidosis. The molecular mechanism(s) responsible for antipsychotic drug-induced weight gain are unknown, but have been hypothesized to be because of interactions of antipsychotic drugs with several neurotransmitter receptors, including 5-HT(2A) and 5-HT(2C) serotonin receptors, H(1)-histamine receptors, alpha(1)- and alpha(2)-adrenergic receptors, and m3-muscarinic receptors. To determine the receptor(s) likely to be responsible for antipsychotic-drug-induced weight gain, we screened 17 typical and atypical antipsychotic drugs for binding to 12 neurotransmitter receptors. H(1)-histamine receptor affinities for this group of typical and atypical antipsychotic drugs were significantly correlated with weight gain (Spearman rho=-0.72; p<0.01), as were affinities for alpha(1A) adrenergic (rho=-0.54; p<0.05), 5-HT(2C) (rho=-0.49; p<0.05) and 5-HT(6) receptors (rho=-0.54; p<0.05), whereas eight other receptors' affinities were not. A principal components analysis showed that affinities at the H(1), alpha(2A), alpha(2B), 5-HT(2A), 5-HT(2C), and 5-HT(6) receptors were most highly correlated with the first principal component, and affinities for the D(2), 5-HT(1A), and 5-HT(7) receptors were most highly correlated with the second principal component. A discriminant functions analysis showed that affinities for the H(1) and alpha(1A) receptors were most highly correlated with the discriminant function axis. The discriminant function analysis, as well as the affinity for the H(1)-histamine receptor alone, correctly classified 15 of the 17 drugs into two groups; those that induce weight gain and those that do not. Because centrally acting H(1)-histamine receptor antagonists are known to induce weight gain with chronic use, and because H(1)-histamine receptor affinities are positively correlated with weight gain among typical and atypical antipsychotic drugs, it is recommended that the next generation of atypical antipsychotic drugs be screened to avoid H(1)-histamine receptors.

DrugBank Data that Cites this Article

Drugs
Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Haloperidol5-hydroxytryptamine receptor 1AProteinHumans
Unknown
Not AvailableDetails
Haloperidol5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Other/unknown
Details
Haloperidol5-hydroxytryptamine receptor 2CProteinHumans
Yes
Not AvailableDetails
Haloperidol5-hydroxytryptamine receptor 6ProteinHumans
Unknown
Not AvailableDetails
Haloperidol5-hydroxytryptamine receptor 7ProteinHumans
Unknown
Not AvailableDetails
HaloperidolAlpha-1A adrenergic receptorProteinHumans
Unknown
Not AvailableDetails
HaloperidolAlpha-2A adrenergic receptorProteinHumans
Unknown
Not AvailableDetails
HaloperidolAlpha-2B adrenergic receptorProteinHumans
Unknown
Not AvailableDetails
HaloperidolAlpha-2C adrenergic receptorProteinHumans
Unknown
Not AvailableDetails
HaloperidolDopamine D2 receptorProteinHumans
Yes
Antagonist
Details
HaloperidolHistamine H1 receptorProteinHumans
Unknown
Not AvailableDetails
HaloperidolMuscarinic acetylcholine receptor M3ProteinHumans
Unknown
Not AvailableDetails
Thiothixene5-hydroxytryptamine receptor 2AProteinHumans
Unknown
Antagonist
Details
Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
Aripiprazole5-hydroxytryptamine receptor 2AKi (nM)8.7N/AN/ADetails
Aripiprazole5-hydroxytryptamine receptor 2CKi (nM)22.4N/AN/ADetails
Aripiprazole5-hydroxytryptamine receptor 6Ki (nM)783.2N/AN/ADetails
AripiprazoleAlpha-2A adrenergic receptorKi (nM)74N/AN/ADetails
AripiprazoleAlpha-2B adrenergic receptorKi (nM)102N/AN/ADetails
AripiprazoleAlpha-2C adrenergic receptorKi (nM)37N/AN/ADetails
AripiprazoleHistamine H1 receptorKi (nM)29.7N/AN/ADetails
Chlorpromazine5-hydroxytryptamine receptor 1AKi (nM)116.4N/AN/ADetails
Chlorpromazine5-hydroxytryptamine receptor 2AKi (nM)8N/AN/ADetails
Chlorpromazine5-hydroxytryptamine receptor 2CKi (nM)25N/AN/ADetails
Chlorpromazine5-hydroxytryptamine receptor 6Ki (nM)20.1N/AN/ADetails
ChlorpromazineHistamine H1 receptorKi (nM)6N/AN/ADetails
ChlorpromazineMuscarinic acetylcholine receptor M3Ki (nM)47N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 1AKi (nM)104.8N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 2AKi (nM)5.4N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 2CKi (nM)17N/AN/ADetails
Clozapine5-hydroxytryptamine receptor 6Ki (nM)17N/AN/ADetails
ClozapineAlpha-2A adrenergic receptorKi (nM)142N/AN/ADetails
ClozapineAlpha-2B adrenergic receptorKi (nM)26N/AN/ADetails
ClozapineAlpha-2C adrenergic receptorKi (nM)34N/AN/ADetails
ClozapineHistamine H1 receptorKi (nM)1.2N/AN/ADetails
ClozapineMuscarinic acetylcholine receptor M3Ki (nM)25N/AN/ADetails
Fluphenazine5-hydroxytryptamine receptor 2AKi (nM)30N/AN/ADetails
Fluphenazine5-hydroxytryptamine receptor 2CKi (nM)1386N/AN/ADetails
Haloperidol5-hydroxytryptamine receptor 2AKi (nM)53N/AN/ADetails
Loxapine5-hydroxytryptamine receptor 1AKi (nM)2456N/AN/ADetails
Loxapine5-hydroxytryptamine receptor 2AKi (nM)7.7N/AN/ADetails
Loxapine5-hydroxytryptamine receptor 2CKi (nM)9.5N/AN/ADetails
Loxapine5-hydroxytryptamine receptor 6Ki (nM)32.9N/AN/ADetails
LoxapineAlpha-2A adrenergic receptorKi (nM)150.8N/AN/ADetails
LoxapineAlpha-2B adrenergic receptorKi (nM)107.6N/AN/ADetails
LoxapineAlpha-2C adrenergic receptorKi (nM)79.9N/AN/ADetails
LoxapineHistamine H1 receptorKi (nM)7N/AN/ADetails
LoxapineMuscarinic acetylcholine receptor M3Ki (nM)122N/AN/ADetails
Molindone5-hydroxytryptamine receptor 1AKi (nM)3797N/AN/ADetails
Molindone5-hydroxytryptamine receptor 2AKi (nM)320N/AN/ADetails
Olanzapine5-hydroxytryptamine receptor 2AKi (nM)2N/AN/ADetails
Olanzapine5-hydroxytryptamine receptor 2CKi (nM)6.8N/AN/ADetails
Olanzapine5-hydroxytryptamine receptor 6Ki (nM)6.28N/AN/ADetails
OlanzapineHistamine H1 receptorKi (nM)2N/AN/ADetails
OlanzapineMuscarinic acetylcholine receptor M3Ki (nM)105N/AN/ADetails
Quetiapine5-hydroxytryptamine receptor 1AKi (nM)431.6N/AN/ADetails
Quetiapine5-hydroxytryptamine receptor 2AKi (nM)101N/AN/ADetails
Quetiapine5-hydroxytryptamine receptor 2CKi (nM)2502N/AN/ADetails
Quetiapine5-hydroxytryptamine receptor 6Ki (nM)1865N/AN/ADetails
QuetiapineAlpha-2A adrenergic receptorKi (nM)3630N/AN/ADetails
QuetiapineAlpha-2B adrenergic receptorKi (nM)746.6N/AN/ADetails
QuetiapineAlpha-2C adrenergic receptorKi (nM)28.7N/AN/ADetails
QuetiapineHistamine H1 receptorKi (nM)11N/AN/ADetails
QuetiapineMuscarinic acetylcholine receptor M3Ki (nM)>10000N/AN/ADetails
Sertindole5-hydroxytryptamine receptor 2AKi (nM)0.58N/AN/ADetails
Sertindole5-hydroxytryptamine receptor 2CKi (nM)0.9N/AN/ADetails
Sertindole5-hydroxytryptamine receptor 6Ki (nM)5.4N/AN/ADetails
Thioridazine5-hydroxytryptamine receptor 2AKi (nM)10N/AN/ADetails
Ziprasidone5-hydroxytryptamine receptor 1AKi (nM)76N/AN/ADetails
Ziprasidone5-hydroxytryptamine receptor 2AKi (nM)0.3N/AN/ADetails
Ziprasidone5-hydroxytryptamine receptor 2CKi (nM)13N/AN/ADetails
Ziprasidone5-hydroxytryptamine receptor 6Ki (nM)60.9N/AN/ADetails
ZiprasidoneAlpha-2A adrenergic receptorKi (nM)160N/AN/ADetails
ZiprasidoneAlpha-2B adrenergic receptorKi (nM)48N/AN/ADetails
ZiprasidoneAlpha-2C adrenergic receptorKi (nM)59N/AN/ADetails
ZiprasidoneHistamine H1 receptorKi (nM)43N/AN/ADetails
ZiprasidoneMuscarinic acetylcholine receptor M3Ki (nM)>10000N/AN/ADetails