PD 176252--the first high affinity non-peptide gastrin-releasing peptide (BB2) receptor antagonist.

In this paper we describe the development of a novel series of non-peptide, "balanced" neuromedin-B preferring (BB1)/gastrin-releasing peptide preferring (BB2) receptor ligands as exemplified by PD 176252. PD 176252, which exhibits nanomolar affinity for both the BB1 (Ki = 0.15 nM) and BB2 (Ki = 1.0 nM) receptors, has been demonstrated to be a competitive antagonist at these bombesin receptor subtypes.

Quantitative structure-activity relationships (QSARs) of N-terminus fragments of NK1 tachykinin antagonists: a comparison of classical QSARs and three-dimensional QSARs from similarity matrices.

The ability of three-dimensional quantitative structure-activity relationships (QSARs) derived from classical QSAR descriptors and similarity indices to rationalize the activity of 28 N-terminus fragments of tachykinin NK1 receptor antagonists was examined. Two different types of analyses, partial least squares and multiple regression, were performed in order to check the robustness of each derived model. The models derived using classical QSAR descriptors lacked accurate quantitative and predictive abilities to describe the nature of the receptor-inhibitor interaction. However models derived using 3D QSAR descriptors based on similarity indices were both robust and significantly predictive. The best model was obtained through the statistical analysis of molecular field similarity indices (n = 28, r2 = 0.846, r(cv)2 = 0.737, s = 0.987, PRESS = 7.102) suggesting that electronic and size-related properties are the most relevant in explaining the affinity data of the training set. The overall quality and predictive ability of the models applied to the test set appear to be very high, since the predicted affinities of three test compounds agree with the experimentally determined affinities obtained subsequently within the experimental error of the binding data.

Rational design of high affinity tachykinin NK1 receptor antagonists.

The rational design of a non-peptide tachykinin NK1 receptor antagonist, [(2-benzofuran)-CH2OCO]-(R)-alpha-MeTrp-(S)-NHCH(CH3)P h (28, PD 154075) is described. Compound 28 has a Ki = 9 and 0.35 nM for the NK1 receptor binding site in guinea-pig cerebral cortex membranes and human IM9, cells respectively (using [125I] Bolton-Hunter-SP as the radioligand). It is a potent antagonist in vitro where it antagonises the contractions mediated by SPOMe in the guinea-pig ileum (KB = 0.3 nM). Compound 28 is active in vivo in the guinea-pig plasma extravasation model, where it is able to block the SPOMe-induced protein plasma extravasation (monitored by Evans Blue) in the bladder with an ID50 of 0.02 mg kg-1 iv.

Conformationally restricted analogues of the potent CCK-B antagonist CI-988.

The synthesis and structure-activity relationships (SAR) for a series of conformationally restricted analogues of the selective cholecystokinin (CCK) antagonist CI-988 and some closely related analogues are described. A series of appropriately substituted cis- and trans-amino decalins are prepared that mimic the through bond distances between the functional groups in the parent compound CI-988 whilst restricting bond rotation. This strategy has led to conformationally more rigid derivatives that have increased CCK-B receptor binding affinity.

Cholecystokinin dipeptoid antagonists: design, synthesis, and anxiolytic profile of some novel CCK-A and CCK-B selective and "mixed" CCK-A/CCK-B antagonists.

The design, synthesis, and structure-activity relationships (SAR) for the development of selective dipeptoid ligands for both of the cholecystokinin (CCK) receptor subtypes CCK-A and CCK-B are described. The SAR developed is used to design a ligand with equal nanomolar binding affinity for both the CCK-A and CCK-B receptors. Example compounds such as [1R-[1 alpha[R*(R*)],2 beta]]-4-[[2-[[3-(1H-indol-3-yl)- 2-methyl-2-[[[(2-methylcyclohexyl)oxy]carbonyl]amino]-1- oxopropyl]-amino]-1-phenylethyl]amino]-4-oxo-butanoic acid (24c), (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28i), and N-[alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy) carbonyl]-D-tryptophanyl]-L-3-(phenylmethyl)-beta-alanine (30m) are CCK-B selective compounds having CCK-B binding affinities of IC50 = 3.9, 0.34, and 0.15 nM with a CCK-A/CCK-B ratio of 464, 53, and 170, respectively. Other compounds such as (1R-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy]carbonyl]- L-tryptophyl]-D-3-(phenylmethyl)-beta-alanine (281) and N-(alpha-methyl-N-[(tricyclo[3.3.1.1]dec-2-yloxy)carbonyl]-L - tryptophyl]-D-3-(phenylmethyl)-beta-alanine (30p) are CCK-A-selective compounds having CCK-A binding affinities of IC50 = 7.9 and 2.82 nM with a CCK-A/CCK-B ratio of 0.007 and 0.01, respectively. Further to these, (1S-trans)-N-[alpha-methyl-N-[[(2-methylcyclohexyl)oxy] carbonyl]-D-tryptophyl]-L-3-(phenylmethyl)-beta-alanine (28h) is a mixed CCK-A/CCK-B ligand with a CCK-A binding affinity of IC50 = 3.9 nM and a CCK-B binding affinity of IC50 = 4.2, producing a CCK-A/CCK-B ratio of unity. The CCK-B selective compounds are shown to be antagonists in electrophysiological tests on the rat ventromedial nucleus of the hypothalamus with an equilibrium constant (Ke) value of 2.8 nM for 30m and are also shown to be anxiolytic in the mouse ligh/dark box test with a minimum effective dose of 0.01 mg/kg, sc, for 30m. The CCK-A selective compounds are also shown to be competitive antagonists by the inhibition of CCK-8S-evoked amylase secretion from pancreatic acinar cells with a Ke value of 16 nM for 30p. In electrophysiological tests on the rat dorsal raphé (an area rich in CCK-A receptors) 30p had a Ke value of 12.8 nM. The mixed CCK-A/CCK-B compound 28h showed antagonistic properties in both CCK-A and CCK-B models; thus it inhibited CCK-8S-evoked amylase secretion from pancreatic acinar cells and is anxiolytic in the light/dark box paradigm.(ABSTRACT TRUNCATED AT 400 WORDS)

Rationally designed "dipeptoid" analogues of CCK. A Free-Wilson/Fujita-Ban analysis of some alpha-methyltryptophan derivatives as CCK-B antagonists.

A Free-Wilson/Fujita-Ban (FW/FB) analysis is reported on 36 "dipeptoid" antagonists of the CCK-B receptor. This series of compounds includes [R-(R*,R*)]-4-[[2-[[3-(1H-indol-3-yl)-2-methyl-1-oxo-2- [[(tricyclo[3.3.1.1] dec-2-yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl]amino]- 4-oxobutanoic acid (CI-988, 1, Figure 1), the first rationally designed non-peptide antagonist of a neuropeptide receptor. The analysis treats the compounds in three parts: the N-terminus, variants on the tryptophan moiety, and the C-terminus. A highly significant correlation was found (n = 36, r2 = 0.97, s = 0.22, F = 57, p = 2 x 10(-8)), suggesting that these three domains of these compounds contribute to binding affinity independently of each other, and are therefore additive in their effects on receptor affinity. The relative free-energies of binding of the individual substituents are calculated from the coefficients of the regression equation. The substitution of D-alpha-methyltryptophan for L-tryptophan increases the free-energy of binding by 3.5 kcal mol-1. This increase in binding energy is explained by a 300-fold difference in conformational entropy between the methylated and desmethyl analogues.

Amide bond replacements incorporated into CCK-B selective "dipeptoids".

This paper describes the chemical synthesis and CCK-B and CCK-A receptor binding affinities of a series of compounds in which the central amide bond of the CCK-B "dipeptoid" ligand tricyclo[3.3.1.1(3,7)]dec-2-yl [R-(R*,S*)]-[2-[[1-(hydroxymethyl)- 2-phenylethyl]amino]-1-(1H-indol-3-ylmethyl)-2-oxoethyl]carb amate (4) (CCK-B IC50 = 852 nM), and tricyclo[3.3.1.1(3,7)]dec-2-yl (R)-[1-(1H-indol-3-ylmethyl)-1-methyl- 2-oxo-2-[(2-phenylethyl)amino]ethyl]carbamate (23) (CCK-B IC50 = 32 nM) is replaced by 11 different amide replacements. These replacements are the methyleneamino (CH2NH), the reverse amide (NHCO), the ester (COO), the N-methylamide (CONMe), the thioamide (CSNH), the N-acetylmethyleneamino (CH2NAc), the cis double bond (CHCH), the ethylene (CH2CH2), the thiolester (COS), the hydroxyethylene (CHOHCH2), and a 4,5-dihydro-1,3-thiazole. Most of the replacements have weaker affinity and reduced selectivity for the CCK-B receptor than the parent amide. However, this affinity can be improved by appending a fumarate side chain to the phenethyl group, e.g. tricyclo[3.3.1.1(3,7)]dec-2-yl-3-(1H-indol-3-yl-methyl)-3-methyl-4 ,9- dioxo-7-phenyl-5,13-dioxa-2,8-diazatetradec-10-enoate (36) (CCK-B IC50 = 38.8 nM). Replacement of the amide of compound 4 with a 4,5-dihydro-1,3-thiazole gives tricyclo[3.3.1.1(3,7)]dec-2-yl [1-[4,5-dihydro-4-(phenylmethyl)-2- thiazolyl]-2-(1H-indol-3-yl)ethyl]carbamate (5), which is selective for the CCK-A receptor (CCK-A IC50 = 125 nM, CCK-B IC50 = 2580 nM, ratio = 21). The methyleneamino and hydroxyethylene replacements, which have been used elsewhere as transition-state inhibitors of enzymes, are poor mimics of the amide in these CCK-B receptor ligands. Some of the steric, lipophilic, and hydrogen bonding properties of amide replacements incorporated into the simple amide, N-methylacetamide, have been quantified with the aid of molecular modeling. These data will contribute to the rational selection of amide bond replacements in other substrates.

The Bannayan syndrome: an autosomal dominant disorder consisting of macrocephaly, lipomas, hemangiomas, and risk for intracranial tumors.

The Bannayan syndrome is a disorder consisting of macrocephaly, alterations of linear growth, and benign mesodermal hamartomas--primarily lipomas and hemangiomas. The purpose of this report is to present a family with the Bannayan syndrome, confirming the genetic etiology of the disorder and demonstrating that affected individuals are at risk for developing intracranial neoplasms. This report brings to seven the number of cases reported in the literature.

A second patient with partial deletion of the short arm of chromosome 3: karyotype 46,XY,del(3)(p25).

A child with monosomy for the distal part of the short arm of chromosome 3 is presented. Altered features include prenatal onset growth deficiency, postaxial polydactyly, ptosis, ear anomalies, and a triangular facial appearance. In addition to generalised delay in psychomotor development, specific problems in visual attention were present. Comparison with the previously reported case suggests that the phenotype observed constitutes a clinically recognisable pattern of malformation.

Presentation of mucopolysaccharidosis VII (beta-glucuronidase deficiency) in infancy.

A child is presented with mucopolysaccharidosis VII (beta-glucuronidase deficiency), bringing to six the number of reported patients with the infantile onset form of this disorder. This patient exhibited the following features, previously unrecognised as part of this syndrome: presentation in the neonatal period, progressive joint contractures, and hydrocephalus. This child's course and data from published reports indicate that mucopolysaccharidosis VII, unlike the other known mucopolysaccharidoses, is clinically recognisable in the newborn period and is most likely to be associated with moderate mental deficiency which does not progress over time.

Short umbilical cord: its origin and relevance.

A short umbilical cord was found in newborns for whom there was evidence of early intrauterine constraint and in those with gross structural or functional limb defects that limited intrauterine movement. These findings were interpreted as showing that umbilical cord growth occurs in response to tensile forces relating to intrauterine space availability and fetal movement during early development. Thus, the finding of a short umbilical cord may indicate diminished fetal movement from either early intrauterine constraint or fetal limb dysfunction.

The vascular pathogenesis of gastroschisis: intrauterine interruption of the omphalomesenteric artery.

Recognition of the disruptive vascular nature of the structural defects associated with gastroschisis and an appreciation of the embryology of the umbilical region suggest that gastroschisis results from an intrauterine interruption of the omphalomesenteric artery. This mechanism accounts for the usual location of gastroschisis to the right of the umbilical cord, the integrity of the rectus muscles in affected children, and many of the clinically observed differences between gastroschisis and omphalocele. The vascular basis of this defect explains its negligible recurrence risk and should alert the clinician to the possibility of concomitant structural defects of a similar pathogenesis.

Compression-related defects from early amnion rupture: evidence for mechanical teratogenesis.

The features of 27 cases of limb/body wall deficiency (formerly termed cyllosomus and pleurosomus) were evaluated and the anomalies were interpreted as being band-related defects and/or compression-related defects. The latter included limb deficiency, body wall deficiency, neural tube defects, scoliosis, postural deformations, growth deficiency, and short umbilical cord. It is hypothesized that the single event of early amnion rupture can explain both the band-related defects and the compression-related defects. Experimental animal studies are in accord with this hypothesis; amnion puncture of rat fetuses during early gestation produces a comparable array of defects. The term amnion rupture sequence is suggested to describe the overall pattern of malformation that results from amnion rupture whether these defects are band related, compression related, or a combination of the two. There is considerable variation in the phenotype of amnion rupture sequence, with limb/body wall deficiency representing the more severe end of the spectrum. It is important to recognize and correctly diagnose amnion rupture sequence because it is usually a sporadic event.

Vascular etiology of disruptive structural defects in monozygotic twins.

Two infants with structural defects previously undescribed in the survivor of a monozygotic twin pair are reported. One infant had hydranencephaly and a spinal cord transection, with an associated dead monozygotic co-twin of 24 weeks gestation; the other child had complete atresia of the colon and a horseshoe kidney, with a deceased co-twin of approximately six weeks gestation. These defects are presumed to be the result of in utero disruption of previously normally formed structures. They occur secondary to vascular exchange from a dead to a living monozygotic twin through placental vascular anastomoses. As illustrated by the two children described, the nature of the vascular defects seen in the survivor of a monozygotic twin pair depends on the time during gestation at which the co-twin dies. Recognition of the disruptive vascular etiology of the structural defects outlined in this report will allow for appropriate counseling with respect to the negligible recurrence risk for similar vascular accidents.

Determining role of the optic vesicle in orbital and periocular development and placement.

Nine patients with aberrations in development and placement of the eyes and periocular structures who also had serious defects in central nervous system development were evaluated in order to better understand normal ocular development. Included were an incompletely developed twin stillborn infant who lacked both eyes and the nose, a stillborn infant with cyclopia hypognathia, 6 spontaneous abortuses with varying degrees of holoprosencephaly, and a 17-year-old male with a serious defect in central nervous system development whose right eye was positioned laterally above the right ear. In all cases, evidence indicates that orbital and periocular structures are determined by the underlying optic vesicle rather than independently derived as has been suggested by previous studies.

Intrauterine constraint and craniosynostosis.

Intrauterine constraint is responsible for a number of structural defects of the craniofacial and peripheral skeleton including plagiocephaly, micrognathia, congenital hip dislocation, and talipes equinovarus. This report describes five infants with serious craniofacial alterations, all attributable to intrauterine constraint. All five children had clinical and laboratory evidence strongly suggestive of craniosynostosis. In three of the five, sutural fusion was documented either at operation or at necropsy. In the other two the clinical course indicated that true synostosis was not present. In all cases the sutural involvement corresponded to the dimension in which head growth had been restricted. This determaination was based upon an assessment of the other craniofacial alterations that were present. The etiology of the intrauterine constrain was different in each case. Factors involved included breech presentation, primagravidity, uterine malformations, amniotic bands, and defects in fetal neuromuscular development, all of which are known to produce fetal deformations. As further evidence of severe constraint, fetal activity was greatly reduced during four of the five pregnancies. There was no history of craniosynostosis in other family members. We propose that in utero compression may lead to a spectrum of craniofacial defects that includes craniosynostosis when the constraint is particularly prolonged. The data suggest that mechanical forces may play a role in the etiology of some cases of craniosynostosis. The fact that head shape spontaneously remolded in one of the five cases suggests further that surgical correction may not be required in all cases in which constraint is the suspected etiology of the deformation. (Neurosurgery, 6: 39-44, 1980).

The Cockayne syndrome: an evaluation of hypertension and studies of renal pathology.

Three children with renal disease, hypertension, and the Cockayne syndrome were evaluated. All patients had severe hypertension; peripheral vein renin was elevated in two patients. Renal biopsy specimens from two patients were studied by light microscopy, electron microscopy, and immunofluoresence. Immunohistologic studies demonstrated deposits of immunoglobulin and complement in the vessels and glomeruli of the first patient; deposits of immunoglobulin and complement were seen in the glomeruli of the third patient. Also electron-dense deposits were seen in the glomerular basement membrane of the third patient. Circulating immune complexes were detected by the Raji cell and Clq binding techniques in this child as well. Both hypertension and renal disease are frequent complications of the Cockayne syndrome.

The amniotic band disruption complex: timing of amniotic rupture and variable spectra of consequent defects.

Seventy-nine patients with the amniotic band disruption complex, including 54 infants with multiple system involvement and 25 with affected limbs alone, were evaluated. No two cases of the disorder were exactly alike. Defects varied from simple digital band constrictions to major craniofacial and visceral defects; fetal death may also occur. Amniotic rupture appeared to cause injury through three basic mechanisms: (1) interruption of normal morphogenesis; (2) crowing of fetal parts; and (3) disruption of previously differentiated structure. Comparison of 35 cases in which the timing of amniotic rupture could be estimated suggests that early amniotic rupture results in multiply affected infants who are frequently aborted or stillborn, whereas later rupture results primarily in limb involvement. Our findings indicate that both the spectrum of the developmental pathology and the nature of fetal outcome are determined by the timing of amniotic rupture. Appreciation of the mechanism which explains the disparate appearances of infants with the amniotic band disruption complex will allow more acurate diagnosis and appropriate counseling with respect to the sporadic nature of the disorder.