PD 158771, a potential antipsychotic agent with D(2)/D(3) partial agonist and 5-HT(1A) agonist actions. I. Neurochemical effects.

The neurochemical effects of a novel dopamine (DA) D(2)-like and serotonin (5-HT) 5-HT(1A) agonist, PD 158771, are described. PD 158771 exhibited affinities for human D(2L), D(3) and D(4.2) receptors expressed in Chinese hamster ovary (CHO)-K1 cells with K(i) (nM) values of 5.

A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent.

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series.

Aminopyrimidines with high affinity for both serotonin and dopamine receptors.

A series of [4-[2(4-arylpiperazin-1-yl)alkyl]cyclohexyl]pyrimidin-2-ylamine s was prepared and found to have receptor binding affinity for D2 and D3 dopamine (DA) receptors and serotonin 5-HT1A receptors. The structural contributions to D2/D3 and 5-HT1A receptor binding of the aminopyrimidine, cycloalkyl, and phenylpiperazine portions of the molecule were examined. From these studies compounds 14, 39, 42, 43, having potent affinity for both DA D2 and 5-HT1A receptors, were evaluated for intrinsic activity at these receptors, in vitro and in vivo.

Pharmacological characterization of PD 152255, a novel dimeric benzimidazole dopamine D3 antagonist.

152255 (E-1,1'-(2-butene-1,4-diyl)bis[2-[4-[3-(1-piperidinyl)propoxy]-phe nyl]-1H-benzimidazole]) exhibited high affinity (Ki = 12.7 nM) for human dopamine (DA) D3 receptors expressed in CHO K1 cells but not for DA D2L receptors (Ki = 565 nM), DA D42 or DA D1 receptors (Ki > 3 microM) and a number of other neurotransmitter receptors. Affinity for human muscarinic receptors was seen in vitro but no functional muscarinic agonist and/or antagonist action was observed in vivo.

Effects of the dopamine D3 antagonist PD 58491 and its interaction with the dopamine D3 agonist PD 128907 on brain dopamine synthesis in rat.

The dopamine (DA) D3 receptor antagonist PD 58491 [3-[4-[1-[4-[2-[4-(3-diethylaminopropoxy)phenyl]benzoimidazol++ +-1-yl-butyl]-1H-benzoimidazol-2-yl]phenoxy]propyl]diethylamine] bound with high affinity and selectivity to recombinant human DA D3 versus D2L and D4.2 receptors transfected into Chinese hamster ovary cells: Ki values of 19.5 nM versus 2,362 and >3,000 nM, respectively.

Substitution of D-Trp32 in NPY destabilizes the binding transition state to the Y1 receptor site in SK-N-MC cell membranes.

The retention rate of the spin label 3-isothiocyanto methyl-2,2,5,5-tetramethyl-1-pyrrolidinyl oxyl spin label (proxyl) attached to the porcine N-acetyl-NPY peptide and the porcine N-acetyl-D-Trp32-NPY peptide at Lys4 was investigated using SK-N-MC neuroblastoma cell membranes containing the Y1 receptor. The release rate of the spin labeled peptides was monitored by electron spin resonance and the KD was determined by a direct radiolabeled NPY displacement binding assay. The analyses show that for the porcine [Ac-Tyr1N epsilon 4-proxyl]-NPY, the KD was 8 x 10(-10) M and koff was 2.

Characterization of Y3 receptor-mediated synaptic inhibition by chimeric neuropeptide Y-peptide YY peptides in the rat brainstem.

1. Neuropeptide Y (NPY) and peptide YY (PYY) act at receptors referred to as Y1 and Y2, while the Y3 receptor is specific to NPY and does not recognize PYY. The effects of NPY, its related peptides and a series of newly constructed chimeric NPY-PYY peptides were examined on excitatory and inhibitory postsynaptic currents (e.

3-[[(4-Aryl-1-piperazinyl)alkyl]cyclohexyl]-1H-indoles as dopamine D2 partial agonists and autoreceptor agonists.

A series of arylpiperazines and tetrahydropyridines joined to indoles by semirigid cycloalkyl spacers were prepared. Target compounds were studied for their ability to bind to the DA D2 receptor in vitro and to inhibit dopamine synthesis and spontaneous locomotor activity in rats. Effects of tether length and relative stereochemistry were assessed for a series of 2-pyridylpiperazines.

Neurochemical and functional characterization of the preferentially selective dopamine D3 agonist PD 128907.

The present study determined the biochemical and pharmacological effects of PD 128907 [R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H- [1]benzopyrano[4,3-b]-1,4-oxazin-9-ol], a dopamine (DA) receptor agonist that shows a preference for the human D3 receptor. In transfected Chinese hamster ovary cells (CHO K1), PD 128907 displaced [3H]spiperone in a biphasic fashion which fit best to a two-site model, generating Ki values of 20 and 6964 nM for the high- and low-affinity sites for the D2L receptors and 1.43 and 413 nM for the corresponding sites for the D3 receptors.

CI-1007, a dopamine partial agonist and potential antipsychotic agent. I. Neurochemical effects.

The receptor binding and biochemical effects of the putative dopamine (DA) partial agonist CI-1007 ([R(+)-1,2,3,6-tetrahydro-4-phenyl- 1-[(3-phenyl-3-cyclohexen-1-yl)methyl]pyridine] maleate) and potential antipsychotic were evaluated with a variety of biochemical methods. In receptor binding studies, CI-1007 bound to rat striatal DA receptors exhibiting a Ki of 3 nM as assessed by inhibition of [3H]N-propylnorapomorphine binding. CI-1007 also exhibited high affinity for cloned human D2L (Ki = 25.

Studies of the active conformation of a novel series of benzamide dopamine D2 agonists.

Analogs of dopamine D2 agonist 11 were prepared in which a rigid trans decalin ring system was used to mimic various conformations of 11. The four rigid analogs where compared for their ability to bind to the DA D2 receptor and to inhibit forskolin-stimulated cAMP formation, a measure of DA agonist activity. Of the four rigid analogs of compound 11, only compound 12b had significant activity in both assays.

Differential interaction of beta 1- and beta 3-adrenergic receptors with Gi in rat adipocytes.

The interaction of beta 1- and beta 3-adrenergic receptors and G(i) proteins was examined in rat adipocytes. In intact adipocytes, cyclic AMP accumulation stimulated by the beta 3-selective agonist, BRL 37344 (BRL), was potentiated by pertussis toxin (PTX), as was the beta 1-sensitive component of isoproterenol (ISO)-stimulated cyclic AMP accumulation. These data suggest that beta 1 and beta 3-receptors interact with both Gs and G(i) in intact adipocytes.