Synthesis of azabicycloalkanone amino acid and azapeptide mimics and their application as modulators of the prostaglandin F2α receptor for delaying preterm birth

The oxytocin receptor (OXTR) and its ligand, oxytocin (OXT), regulate reproductive physiology (i.e., parturition and lactation) and sociosexual behaviors. To define the essential functions of OXTR, we generated mice with a null mutation in the Oxtr gene (Oxtr(-/-)) and compared them with OXT-deficient (Oxt(-/-)) mice. Oxtr(-/-) mice were viable and had no obvious deficits in fertility or reproductive behavior. Oxtr(-/-) dams exhibited normal parturition but demonstrated defects in lactation and maternal nurturing. Infant Oxtr(-/-) males emitted fewer ultrasonic vocalizations than wild-type littermates in response to social isolation. Adult Oxtr(-/-) males also showed deficits in social discrimination and elevated aggressive behavior. Ligand Oxt(-/-) males from Oxt(-/-) dams, but not from Oxt(+/-) dams, showed similar high levels of aggression. These data suggest a developmental role for the OXT/OXTR system in shaping adult aggressive behavior. Our studies demonstrate that OXTR plays a critical role in regulating several aspects of social behavior and may have important implications for developmental psychiatric disorders characterized by deficits in social behavior.

Very-low-birth-weight infants (those weighing less than 1500 g) born during the initial years of neonatal intensive care have now reached young adulthood. We compared a cohort of 242 survivors among very-low-birth-weight infants born between 1977 and 1979 (mean birth weight, 1179 g; mean gestational age at birth, 29.7 weeks) with 233 controls from the same population in Cleveland who had normal birth weights. We assessed the level of education, cognitive and academic achievement, and rates of chronic illness and risk-taking behavior at 20 years of age. Outcomes were adjusted for sex and sociodemographic status. Fewer very-low-birth-weight young adults than normal-birth-weight young adults had graduated from high school (74 percent vs. 83 percent, P=0.04). Very-low-birth-weight men, but not women, were significantly less likely than normal-birth-weight controls to be enrolled in postsecondary study (30 percent vs. 53 percent, P=0.002). Very-low-birth-weight participants had a lower mean IQ (87 vs. 92) and lower academic achievement scores (P<0.001 for both comparisons). They had higher rates of neurosensory impairments (10 percent vs. <1 percent, P<0.001) and subnormal height (10 percent vs. 5 percent, P=0.04). The very-low-birth-weight group reported less alcohol and drug use and had lower rates of pregnancy than normal-birth-weight controls; these differences persisted when comparisons were restricted to the participants without neurosensory impairment. Educational disadvantage associated with very low birth weight persists into early adulthood.

G protein-coupled receptors (GPCRs) represent the largest family of cell-surface receptors. These receptors are natural allosteric proteins because agonist-mediated signaling by GPCRs requires a conformational change in the receptor protein transmitted between two topographically distinct binding sites, one for the agonist and another for the G protein. It is now becoming increasingly recognized, however, that the agonist-bound GPCR can also form ternary complexes with other ligands or "accessory" proteins and display altered binding and/or signaling properties in relation to the binary agonist-receptor complex. Allosteric sites on GPCRs represent novel drug targets because allosteric modulators possess a number of theoretical advantages over classic orthosteric ligands, such as a ceiling level to the allosteric effect and a potential for greater GPCR subtype-selectivity. Because of the noncompetitive nature of allosteric phenomena, the detection and quantification of such effects often relies on a combination of equilibrium binding, nonequilibrium kinetic, and functional signaling assays. This review discusses the development and properties of allosteric receptor models for GPCRs and the detection and quantification of allosteric effects. Moreover, we provide an overview of the current knowledge regarding the location of possible allosteric sites on GPCRs and candidate endogenous allosteric modulators. Finally, we discuss the potential for allosteric effects arising from the formation of GPCR oligomers or GPCRs complexed with accessory cellular proteins. It is proposed that the study of allosteric phenomena will become of progressively greater import to the drug discovery process due to the advent of newer and more sensitive GPCR screening technologies.