Multiple forms of phosphofructokinase in developing rabbit and guinea pig tissues.

Multiple forms of phosphofructokinase in striated muscle and cardiac muscle of developing rabbit (Oryctolagus cuniculus) undergo changes with development, but not in brain and liver. The cardiac muscle of the 1-day-old rabbit contains phosphofructokinase A₄ together with the four hybrid forms which were tentatively called A₃C, A₂C₂, AC₃, and C₄. In older animals, phosphofructokinase C₄ disappears first, followed by the hybrid forms, and only phosphofructokinase A₄ persists in the adult animal. Both phosphofructokinase A₄ and phosphofructokinase C₄, as well as their hybrid forms, are present in developing embryonic brain and also in the brains of adult animals. Developing rabbit liver contains a single form of phosphofructokinase, but two isoenzymes are consistently seen in guinea pig liver. In striated muscle from fetal and 1-day-old rabbit, two isoenzymes are found, tentatively identified as A₄ and the A₃C hybrid. The results suggest that fetal phosphofructokinase A₄ and phosphofructokinase C₄, and their hybrids, might be present in striated muscle. Guinea pig tissues show a pattern of phosphofructokinase isoenzymes different from that in rabbit tissues.     

Synthesis and pharmacological evaluation of piperidine (piperazine)-amide substituted derivatives as multi-target antipsychotics

We report the optimisation of a series of novel amide-piperidine (piperazine) derivatives using the multiple ligand approach with dopamine and serotonin receptors. Of the derivatives, compound 11 exhibited high affinity for the D₂, 5-HT_1A, and 5-HT_2A receptors, but low affinity for the 5-HT_2C and histamine H₁ receptors and human ether-a-go-go-related gene (hERG) channels. In vivo, compound 11 reduced apomorphine-induced climbing, MK-801-induced hyperactivity and DOI-induced head twitching without observable catalepsy, even at the highest dose tested. In addition, it exhibited suppression in a CAR test. Furthermore, in a novel object recognition task, it displayed procognition properties. Therefore, compound 11 is a promising candidate multi-target antipsychotic.     

Synthesis and evaluation of a series of 2-substituted-5-thiopropylpiperazine (piperidine)-1,3,4-oxadiazoles derivatives as atypical antipsychotics

Background

It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D₂ and D₃, serotonin 5-HT_1A and 5-HT_2A receptors with low affinity for the serotonin 5-HT_2C and H₁ receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.

Methodology/Principal Findings

A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D₂, 5-HT_1A and 5-HT_2A receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D₂, 5-HT_1A and 5-HT_2A receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D₃ receptor, and low affinity for serotonin 5-HT_2C and H₁ receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties.

Conclusions/Significance

Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.     

Comparison of tryptic peptide maps of eight isoperoxidases from tobacco tissue cultures

Eight isoperoxidases from tobacco suspension culture WR-132 (termed C_n, C₃, C₄, A_c, and A_f) and tobacco callus culture W-38 (termed A₁, A₂, and A₃) have been subjected to trypsin digestion followed by peptide mapping. The peptide maps of isoperoxidases A_f and A₃ are identical. All other isoperoxidases do not appear to be dramatically dissimilar in certain portions of their sequence, since many matching peptides have been found when various isoperoxidases are cross-compared. However, only two, and possibly three, highly homologous peptides are present in all of the isoperoxidases.     

Fate of radioactive gibberellin a(1) in maturing and germinating seeds of peas and Japanese morning glory

Radioactive gibberellin A₁ (³H-GA₁) was injected into excised fruits of peas and Japanese morning glory. These were then grown in sterile culture to maturity and the label was followed in the seeds during further development and subsequent germination. During development of both pea and morning-glory seeds a large part of the radioactivity became associated with the aqueous fraction, while another part of the ³H-GA₁ was converted into 2 new, acidic, biologically active compounds, designated X₁ and X₂. A relatively small part of the neutral compounds could be converted back to ³H-GA₁, X₁, and X₂ by means of mild acid hydrolysis. During germination of pea and morning-glory seeds, part of the bound compounds was released in the form of ³H-GA₁, X₁ and X₂ while, particularly during rapid seedling growth, a further conversion of ³H-GA₁, mainly to X₁, took place. In pea seedlings, growth during the first 2 to 3 days after imbibition was not affected by Amo-1618, an inhibitor of gibberellin biosynthesis. This, in conjunction with the findings on the interconversions between free and bound ³H-GA₁ suggests that, at least in peas, early seedling growth may at least partly be regulated by gibberellins released from a bound form which was formed during seed development.     

FOUR PROTEIN POLYMORPHISMS IN PIGEON BRAIN EXTRACTS DETECTED BY TWO-DIMENSIONAL GEL ELECTROPHORESIS

Abstract— Proteins of the brain extracts of 85 individual pigeons (Columba livia) were mapped by two-dimensional gel electrophoresis. The method is a modification of O'Farrell 'S technique and separates proteins first by charge and then by molecular weight. There were three proteins, A, B and D which had each a variant form. The positions of these six proteins on the gel corresponded to the following pH values and molecular weight values: protein A₁, 6.4/43,000; A₂, 6.6/43,000; B₁, 5.7/41,000; B₂, 5.8/40,000; D₁, 6.2/22,000; D₂, 6.2/21,000. The variants are genetically determined, since protein A, B and D each occurred in three phenotypes (A₁, A₁A₂ and A₂; B₁, B₁B₂ and B₂; D₁, D₁D₂ and D₂) corresponding to the three possible genotypes. From the observed frequencies of the phenotypes the following allele frequencies were calculated: allele A₁, 72%; A₂, 28%; B₁, 15%; B₂, 85%; D₁, 74%; D₂, 26%. A fourth protein named C occurred in four different forms (C₁, 7.2/37,000; C₂, 7.2/36,000; C₃, 7.1/37,000; C₄, 7.1/36,000) and six phenotypes (C₁, C₁C₂, C₂, C₁C₃, C₂C₃ and C₄C₃). This polymorphism is also interpreted as being genetically determined. The four alleles coding for the four protein C forms had the following frequencies: allele C₁, 62%; C₂, 27%; C₃, 10.5%; C₄, 0.5%.     

Molecular interactions of the quinone electron acceptors QA,QB, and QC in photosystem II as studied by the fragment molecular orbital method

Molecular interactions of the three plastoquinone electron acceptors, Q_A, Q_B, and Q_C, in photosystem II (PSII) were studied by fragment molecular orbital (FMO) calculations. Calculations at the FMO-MP2/6-31G level using PSII models deduced from the X-ray structure of the PSII complexes from Thermosynechococcus elongatus provided the binding energies of Q_A, Q_B, and Q_C as ?56.1, ?37.9, and ?30.1 kcal/mol, respectively. The interaction energies with surrounding fragments showed that the contributions of lipids and cofactors were 0, 24 and 45 % of the total interaction energies for Q_A, Q_B, and Q_C, respectively. These results are consistent with the fact that Q_A is strongly bound to the PSII protein, whereas Q_B functions as a substrate and is exchangeable with other quinones and herbicides, and the presence of Q_C is highly dependent on PSII preparations. It was further shown that the isoprenoid tail is more responsible for the binding than the head group in all the three quinones, and that dispersion forces rather than electrostatic interactions mainly contribute to the stabilization. The relevance of the stability and molecular interactions of Q_A, Q_B, and Q_C to their physiological functions is discussed.     

Two New Xylanases with Different Substrate Specificities from the Human Gut Bacterium Bacteroides intestinalis DSM 17393

Xylan is an abundant plant cell wall polysaccharide and is a dominant component of dietary fiber. Bacteria in the distal human gastrointestinal tract produce xylanase enzymes to initiate the degradation of this complex heteropolymer. These xylanases typically derive from glycoside hydrolase (GH) families 10 and 11; however, analysis of the genome sequence of the xylan-degrading human gut bacterium Bacteroides intestinalis DSM 17393 revealed the presence of two putative GH8 xylanases. In the current study, we demonstrate that the two genes encode enzymes that differ in activity. The xyn8A gene encodes an endoxylanase (Xyn8A), and rex8A encodes a reducing-end xylose-releasing exo-oligoxylanase (Rex8A). Xyn8A hydrolyzed both xylopentaose (X₅) and xylohexaose (X₆) to a mixture of xylobiose (X₂) and xylotriose (X₃), while Rex8A hydrolyzed X₃ through X₆ to a mixture of xylose (X₁) and X₂. Moreover, rex8A is located downstream of a GH3 gene (xyl3A) that was demonstrated to exhibit β-xylosidase activity and would be able to further hydrolyze X₂ to X₁. Mutational analyses of putative active site residues of both Xyn8A and Rex8A confirm their importance in catalysis by these enzymes. Recent genome sequences of gut bacteria reveal an increase in GH8 Rex enzymes, especially among the Bacteroidetes, indicating that these genes contribute to xylan utilization in the human gut.     

Influence of an inhibitor of gibberellin biosynthesis, paclobutrazol, on apple seed gibberellin content

Tissue-culture-propagated own-rooted cv. Spartan apple trees (Malus domestica Borkh.) planted in 1979 were treated in 1983 and 1985 via a soil-line trunk drench with the plant growth retardant paclobutrazol [(2RS, 3RS)-1-(4-chlorophenyl)-4.4-dimethyl-2-(1,2, 4-triazol-1-yl) pentan-3-ol]. Seeds of immature fruits from untreated and treated trees were sampled in 1989 ca 75 days after full bloom. After seeds were freeze-dried, gibberellins (GAs) were extracted, purified and fractionated via C₁₈ reversed-phase high-performance liquid chromatography (HPLC). Gibberellins A₁, A₃, A₄, A₇, A₈, A₉, A₁₅, A₁₇, A₁₉, A₂₀, A₂₄, A₃₄, A₃₅, A₄₄, A₅₁, A₅₃, A₅₄, A₆₁, A₆₂, A₆₃ and A₆₈ were identified by using C₁₈ HPLC, gas chromatography-selected ion monitoring and Kovats retention indices. Eight of the GAs identified were also quantified by using deuterated internal standards. The paclobutrazol applications caused a 55% reduction of vegetative shoot elongation in 1989, but both treated and untreated trees had developed a biennial bearing pattern by that time (heavy bloom or “on year’in 1989). Levels of early 13-hydroxylation pathway GAs, viz. GA₅₃, GA₁₉, GA₂₀, GA₁ and also GA₃, were not altered by treatment. However, GA₄, GA₇ and GA₉ were increased 13.4, 6.5 and 3.8 times, respectively, in seeds of fruit from treated compared to untreated trees.     

F-tests for Hypotheses with Block Matrices and Under Conditions of Orthogonality in the General Multivariate Gauss-Markoff Model

The multivariate general Gauss-Markoff (MGM) model (U, XB, ∑?σ²V) when the matrices V ≥ 0 and ∑ > 0 are known and the scalar σ² > 0 is unknown, is considered. The present paper is a continuation of two earlier works (Oktaba, 1988a, b). If XB = X₁Σ + X₂Δ, then the F-test for verification the hypothesis WΣA = 0 is presented. Moreover, under conditions of orthogonality the decomposition of the matrix S_A (?BCA)′L^?(?BCA) into the sum of s = r(L) matrices is given, where ?BCA is the estimator of the parametric estimable functions ?BCA, Cov (?BCA) = A′ ∑?σ²L = ?C₄?′, B? = (X′T^?X)^?X′T^?U, C₄ = (X′T^?X)^?M, where M = M′ is any arbitrary matrix such that R(X) ? R(T), T=V+XMX′; T^? is any c-inverse. R(A) is the linear space generated by the colums of A. Then under additional assumption on normality of U the statistics F for testing ?BA = 0 is deduced. Under conditions of normality of U and decomposition of S_A, the statistics F₁, …, F_s for the hypotheses jⁱ BA = 0 (i = 1,…, s) are established.     

The Structure of Gibberellin A23 and the Biological Properties of 3,13-Dihydroxy C20-Gibberellins

Two aldehydic C₂₀-gibberellins, L-2 and L-4, were isolated from the immature fruits of yellow lupine (Lupinus luteus L.). L-2 was shown to have the structure II and named gibberellin A₂₃. L-4 was identified as gibberellin A₁₉(VI). Two new C₂₀-gibberellins, tentatively called 3,13-dihydroxy GA₁₅(IV) and 13-hydroxy GA₁₅(VIII), were derived from gibberellins, A₂₃ and A₁₉, respectively. The biological activities of four 3,13-dihydroxy C₂₀-gibberellins-GA₁₈(I), GA₂₃(II), GA₂₈(III) and 3,13-dihydroxy GA₁₅(IV), which were isolated from the fruits except for 3,13-dihydroxy GA₁₅—were compared in six gibberellin bioassays.     

Ribonuclease activities in bean roots

Vicia faba meristematic and elongating root cells (zones 0–4 and 10–20 mm) contained one nuclease (A₁) and four ribonucleases (A₂, A₃, C₁, C₂). When the overall activity of each enzyme was expressed per cell, the elongating cells contained 4-, 4-, 4-, 10- and 17-fold more activity than meristematic cells for A₁, C₁, C₂, A₂ and A₃, respectively.     

Effect of Climbing Fiber Deprivation on Release of Endogenous Aspartate, Glutamate, and Homocysteate in Slices of Rat Cerebellar Hemispheres and Vermis

Aspartate (Asp) and/or glutamate (Glu) have been proposed as putative excitatory transmitters released from synaptic terminals of the olivo-cerebellar climbing fiber afferents to the Purkinje cells. Investigations of the climbing fiber transmitter(s) separately for hemispheres and vermis were performed to examine whether the current controversy over the role of Asp as a neurotransmitter in the climbing fibers may be due to topographic differences. K(+)-induced Ca2(+)-dependent release of endogenous substances was investigated in slices of cerebellar hemisphere and vermis of control rats and those deprived of climbing fibers by 3-acetylpyridine (3-AP) treatment. A release of Asp and Glu, as well as a small but significant release of homocysteic acid (HCA) was confirmed in control rats. Climbing fiber deprivation by 3-AP treatment reduced the stimulated release of Asp by 48% in slices of cerebellar hemispheres, but not in vermis. Climbing fiber deprivation completely abolished the release of HCA in both hemispheres and vermis. The release of HCA, Asp, and Glu from slices of control and climbing fiber-deprived rats evoked by 50 mM K+ was greater than 90% Ca2(+)-dependent. These results support the hypothesis that Asp is a transmitter candidate of the climbing fibers projecting to the cerebellar hemispheres, but not to the vermis, and provide the first evidence that HCA can be linked to a specific pathway.     

Synthesis of (NBu4)2[Pd2(μ-Br)2(C6X5)2Br2] (X=F,Cl), new and more versatile precursors of pentahalophenyl derivatives of palladium(II)

The title compounds (1, X=F; 2, X=Cl) were obtained in quantitative yield by refluxing together (NBu₄)₂[Pd₂(μ-Br)₂(C₆X₅)₄] and (NBu₄)₂[Pd₂(μ-Br)₂Br₄]. Treatment of 1 or 2 with AgClO₄ (Pd:Ag= 1:1) gave solutions which behaved as containing ‘Pd(C₆X₅)Br’. 1, 2 and the ‘Pd(C₆X₅)Br’ solutions were checked as precursors of mono-pentahalophenyl derivatives, yielding a variety of complexes [Pd(C₆X₅)Br(L-L)] (L-L=bipy, tmen, dpe, COD), [Pd(C₆X₅)BrL₂] (L=p-TolNH₂, py, PPh₃, AsPh₃, SbPh₃), [Pd₂(μ-Br)₂(C₆X₅)₂L₂] (X=F, L=AsPh₃; X=Cl, L=SbPh₃) and (NBu₄)[Pd(C₆X₅)Br₂L] (X=F, L= py, AsPh₃, SbPh₃; X=Cl, L=p-TolNH₂, py, PPh₃, AsPh₃, SbPh₃). The solutions of ‘Pd(C₆X₅)Br’ proved to be the best general precursors of complexes [Pd(C₆X₅)BrL₂] although complexes with OPPh₃ could not be obtained.     

Energy supply of the okapi in captivity: intake and digestion trials

In the nutrition of browsing ruminants in captivity, adequate nutrient digestibility and energy content of diet is debated. Problems related to energy‐provision and low forage intake have been reported for the okapi and other browsers like the giraffe, particularly during winter. High‐fiber concentrates like unmolassed beet pulp have some potential to improve the nutritional management of these species. Using a total of six okapis in captivity, seven feeding trials were carried out at two facilities (A+B) on a structured but opportunistic base. Three trials (A₁, A₂, B₁) were conducted when animals were fed their regular diet including grain based energy concentrates, fruits and vegetables, and alfalfa (Medicago sativa) hay. Two trials (A₅, B₂) examined the effect of unmolassed beet pulp, and two (A₃,₄) examined the effect of unmolassed beet pulp+fresh browse. Daily intake and feces production were quantified over 8–12 days. Samples were analyzed for dry matter, crude ash, neutral detergent fiber (NDF)/acid detergent fiber (ADF)/acid detergent lignin (ADL), crude protein, and gross energy. Metabolizable energy content of diets was estimated via a factor (0.83) from digestible energy. The proportion of beet pulp in diets was 13% (A₃), 24% (A₄), 20% (A₅), and 21% (B₂). Browse proportion was 11% (A₃) and 32% (A₄). Daily feed intake ranged between 1.5–1.7% of body weight (BW), digestibility of organic matter between 61–74%. Digestibility of fiber (NDF) was higher in beet pulp diets (A₃=39%, A₄=60%, A₅=54%, B₂=61%) than in the others (A₁=48%, A₂=33%, B₁=48%). Supply of metabolizable energy (ME) ranged between 0.50–0.70 MJ ME/(kg BW^0.75*day), meeting energy requirements of okapis of 0.50–0.53 MJ ME/(kg BW^0.75*day) in general. Diets with beet pulp+browse were not found to be highest, but in the upper level of the range of forage proportions of this study. Palatable browse species were preferred over all other feedstuff offered. The use of unmolassed beet pulp as energy‐concentrate for browsing ruminants like the okapi can be recommended because diets high in this high‐fibre feedstuff resulted in adequate energy intakes. Zoo Biol 0:1–14, 2006. © 2006 Wiley‐Liss, Inc.     

Prostaglandin removal and metabolism by isolated perfused rat lung

We have investigated the mechanism(s) involved in the removal of prostaglandins (PG) from the pulmonary circulation by the lung. Unidirectional fluxes of PG from the circulation into the lung are measured in an isolated perfused rat lung preparation. Evidence is presented which suggests that a transport system for PG exists in lung tissue. This transport system is responsible for the removal of some PG from the circulation by the lung. PGE₁ and PGF_2α are substrates for this system, whereas PGB₁, PGA₁, and 15-keto-PGF_2α are not. Since PGA₁ is a substrate for the intracellular PG dehydrogenase, the selectivity of the lung's metabolism system for circulating PG is probably due to the selectivity of the transport system for PG. It is shown that the percentage of the pulmonary arterial concentration (C_A) of PGE₁ or PGF_2α that is metabolized on passage through the pulmonary circulation decreases rapidly as C_A increases. When the lungs were perfused with PGE₁ (PGF_2α), the metabolites detected in the venous effluent were 15-keto-PGE₁ (PGF_2α) and 15-keto-13,14-dihydro-PGE₁ (PGF_2α). The time course pattern of the appearance of metabolites in the venous effluent after the initiation of a constant C_A, and the relative concentrations of the metabolites in the venous effluent, were examined as a function of C_A.     

Selective Increase of α2A-Adrenoceptor Agonist Binding Sites in Brains of Depressed Suicide Victims

Abstract: The α_2A- and α_2C-adrenoceptor subtypes were evaluated in postmortem brains from suicides with depression (n = 22), suicides with other diagnoses (n = 12), and controls (n = 26). Membrane assays with the antagonist [³H]RX821002 (2-[³H]methoxyidazoxan) suggested the presence of α_2A-adrenoceptors in the frontal cortex and both α_2C-adrenoceptors and α_2A-adrenoceptors in the caudate. The proportions in caudate were similar in controls (α_2A, 86%; α_2C, 14%), depressed suicides (α_2A, 91%; α_2C, 9%), and suicides with other diagnoses (α_2A, 88%; α_2C, 12%). Autoradiography of [³H]RX821002 binding under α_2B/C-adrenoceptor-masking conditions confirmed the similar densities of α_2A-adrenoceptors in the cortex, hippocampus, and striatum from controls and suicides. In the frontal cortex of depressed suicides, competition of [³H]RX821002 binding by (?)-adrenaline revealed a greater proportion (61 ± 9%) of α_2A-adrenoceptors in the high-affinity conformation for agonists than in controls (39 ± 5%). Simultaneous analysis with the agonists [³H]clonidine and [³H]UK14304 and the antagonist [³H]RX821002 in the same depressed suicides confirmed the enhanced α_2A-adrenoceptor density when evaluated by agonist, but not by antagonist, radioligands. The results indicate that depression is associated with a selective increase in the high-affinity conformation of the brain α_2A-adrenoceptors.     

The Metabolism of the Germinating Oil Palm (Elaeis guineensis) Seedling : In Vivo Studies

The metabolism of ¹⁴C-labeled fatty acids and triacylglycerols was followed in intact germinating oil palm seedlings as well as in tissue slices. In the germinating seedling, the shoot contained a normal pattern of membrane fatty acids (mainly C₁₆, C_18:1, C_18:2) but the kernel contained about 68% C₁₂ and C₁₄ fatty acids. Haustorium fatty acids were intermediate between the two. [¹⁴C]Acetate was actively metabolized by shoot and haustorium slices but not so actively by the kernel. Approximately 9% to 17% was converted to water-soluble substances, 4% to 6% to CO₂, and 0.5% to 5.9% to lipids. The fatty acids synthesized in the shoot and haustorium were mainly C₁₆, C₁₈, and C_18:1 fatty acids but in the kernel about 18% to 32% of the ¹⁴C-fatty acids were C₁₂ fatty acids.

[¹⁴C]Lauric acid was absorbed and metabolized by haustorium slices and by the haustorium in intact seedlings; it was partly esterified to triacylglycerols and also converted to water-soluble substances and insoluble tissue material. In contrast, tri-[¹⁴C]laurin was absorbed but not metabolized. The haustorium also absorbed other fatty acids but the longer chain (C₁₆ and C₁₈) fatty acids were not esterified or metabolized further. Preincubation of the haustorium with plant hormones or in the presence of kernel tissue did not alter its inactivity towards tri-[¹⁴C]laurin.

When tri-[¹⁴C]laurin or [¹⁴C]lauric acid were injected into the seed or the shoot, there was no movement or radioactivity to other parts of the seedling. When injected into the shoot, but not into the seed, tri-[¹⁴C] laurin was hydrolyzed and partly metabolized to water-soluble substances.

     

Evolution of the multidomain protein wheat germ agglutinin

Summary We compared the homologous amino acid sequences of hevein and each of the four domains (A, B, C, and D) of wheat germ agglutinin and used them to construct a pseudophylogenetic tree relating these sequences to a hypothetical common ancestor sequence. In the crystal structure of the wheat germ agglutinin dimer, six pseudo-twofold rotational symmetry axes have previously been located in addition to the true twofold axis. Four of these relate two nonidentical domains to each other in each of the four possible pairs constituting the sugar-binding sites (A₁D₂, A₂D₁, B₁C₂, and B₂C₁). The remaining two relate contiguous unique pairs of sugar-binding sites to each other (A₁D₂ to B₁C₂, and A₂D₁ to B₂C₁). These latter two sets of pairs are related to each other by the true twofold axis. Side chains that mediate sugar binding in the interfaces of each of the four pairs were found to be largely conserved. The sequence homology, taken together with these pseudo-symmetry elements in the dimer structure, suggests a pathway for the evolution of the four-domain molecule from a single-domain dimer that can be correlated with simultaneous development of the saccharide-binding sites.     

Synthesis and binding affinity of potential atypical antipsychotics with the tetrahydroquinazolinone motif

A series of 8 new tetrahydroquinazolinone derivatives was synthesized and evaluated for binding affinity to D₂ and 5-HT_2A human receptors; in addition, some properties related to blood–brain barrier penetration were calculated. From the results of these assays, three compounds were selected for further binding tests on D₁, D₃, and 5-HT_2C human receptors, which are thought to be involved in schizophrenia. From these data, compound 19b emerged as the most promising candidate based on its good binding affinities for D₁, D₂, and D₃ receptors, high affinity for 5-HT_2A, low affinity for 5-HT_2C receptors, and a Meltzer’s ratio characteristic of an atypical antipsychotic profile.