ABSTRACT
A series of compounds containing privileged scaffolds of the known histamine H(1) receptor antagonists cetirizine, mianserin, ketotifen, loratadine, and bamipine were synthesized for further optimization as ligands for the related biogenic amine binding dopamine D(3) receptor. A pharmacological screening was carried out at dopamine D(2) and D(3) receptors. In the preliminary testing various ligands have shown moderate to high affinities for dopamine D(3)receptors, for example, N-(4-{4-[benzyl(phenyl)amino]piperidin-1-yl}butylnaphthalen-2-carboxamide (19a) (hD(3)K(i)=0.3 nM; hD(2)K(i)=703 nM), leading to a selectivity ratio of 2343.
Subject(s)
Drug Design , Histamine H1 Antagonists/chemical synthesis , Histamine H1 Antagonists/pharmacology , Receptors, Dopamine D3/antagonists & inhibitors , Amines/chemistry , Animals , Binding, Competitive , CHO Cells , Cell Line , Cetirizine/chemical synthesis , Cetirizine/chemistry , Cetirizine/pharmacology , Cricetinae , Cricetulus , Dopamine D2 Receptor Antagonists , Drug Evaluation, Preclinical , Histamine H1 Antagonists/chemistry , Humans , Ketotifen/chemical synthesis , Ketotifen/chemistry , Ketotifen/pharmacology , Ligands , Loratadine/chemical synthesis , Loratadine/chemistry , Loratadine/pharmacology , Mianserin/chemical synthesis , Mianserin/chemistry , Mianserin/pharmacology , Molecular Structure , Piperidines/chemical synthesis , Piperidines/chemistry , Piperidines/pharmacology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A central element in the pathophysiology of Alzheimer's disease (AD) is the formation of amyloid plaques, which result from abnormal processing of the amyloid precursor protein (APP). The processing of APP is largely provided by three key enzymes, namely the alpha-, beta-, and gamma-secretases. As the latter two contribute to the formation of neurotoxic Abeta fragments while alpha-secretase does not, a decrease in the amyloidogenic products can be brought about either by inhibition of the beta- and gamma-secretases or through the activation of alpha-secretase. It is now known that the activation of protein kinase C (PKC) enhances alpha-secretase activity and therefore represents a possible target for the development of agents urgently needed for the treatment of this devastating neurodegenerative disorder. In the present study, new benzolactam-V8-based PKC activators were synthesized and tested for their binding affinity toward PKCalpha. All compounds tested showed binding values in the nanomolar concentration range. In accordance with previous publications, 9-substitution dramatically increased PKC binding affinity in comparison with the corresponding 8-substituted analogues. In addition to the location of the side chain on the aromatic ring, the binding affinities of these benzolactams were found to depend on the orientation, length, and electronic properties of this appendage. An interesting decrease in binding affinity was found for the 9-thienyl analogue 13, suggesting adverse electronic interactions of the sulfur atom with PKC or parts of the cellular membrane.
Subject(s)
Lactams/chemical synthesis , Lactams/pharmacology , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Alzheimer Disease/drug therapy , Chromatography, High Pressure Liquid , Humans , Lactams/therapeutic use , Ligands , Magnetic Resonance Spectroscopy , Mass Spectrometry , Protein Kinase Inhibitors/therapeutic useABSTRACT
Based on N-alkylated 1,2,3,4-tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, (E)-3-(4-iodophenyl)-N-(4-(1,2,3,4-tetrahydroisoquinolin-2-yl)butyl)acrylamide (51) has high affinity (Ki(hD3)=12 nM) and a 123-fold preference for the D3 receptor relative to the D2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D3-receptor-related in vitro and in vivo investigations.
Subject(s)
Receptors, Dopamine D2/agonists , Receptors, Dopamine D2/metabolism , Tetrahydroisoquinolines/metabolism , Tetrahydroisoquinolines/pharmacology , Animals , CHO Cells , Cricetinae , Humans , Ligands , Molecular Structure , Piperazines/chemistry , Piperazines/metabolism , Piperazines/pharmacology , Receptors, Dopamine D3 , Tetrahydroisoquinolines/chemistryABSTRACT
In monkeys rendered parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), expression of the dopamine D3 receptor was decreased. However, levodopa-induced dyskinesia (LID), similar to the debilitating and pharmacoresistant involuntary movements elicited after long-term treatment with levodopa in patients with Parkinson disease (PD), was associated with overexpression of this receptor. Administration of a D3 receptor-selective partial agonist strongly attenuated levodopa-induced dyskinesia, but left unaffected the therapeutic effect of levodopa. In contrast, attenuation of dyskinesia by D3 receptor antagonists was accompanied by the reappearance of PD-like symptoms. These results indicated that the D3 receptor participated in both dyskinesia and the therapeutic action of levodopa, and that partial agonists may normalize D3 receptor function and correct side effects of levodopa therapy in patients with PD.
