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The relationship between parents' stated sex preferences for children and actual parental behaviour towards sons and daughters is examined among the Mukogodo, a group of traditional pastoralists in rural Kenya. Although their cultural values are male-centered and they tend to express a preference for sons, Mukogodo parents actually appear to be more solicitous of daughters, and the Mukogodo have a strongly female-biased childhood sex ratio. Studies of stated sex preferences should therefore be coupled with attempts to assess actual parental investment in sons and daughters. [ABSTRACT FROM AUTHOR]

Tests the evolutionary biological hypothesis--that culturally defined values and goals are proximate means of enhancing reproductive success--on data from the Mukogodo, a small group of Maa-speaking pastoralists in north-central Kenya who value the accumulation of livestock. Livestock wealth correlation to reproductive success; Polygyny among wealthier men; Ethnographic background; Data collection; Wealth, status, and reproductive success; Details.

Comments on the need for sperm donors and how evolution is not as quick to adapt as technology. Example of armadillo's survival tactics and its conflict with cars; Changing environment; Economic and social changes; Stone Age physiology in technological age; More.

In recent years there has been much interest in investigating the extent to which social status or prestige are related to an individual's degree of integration in social networks. It has been shown that, among hunter-gatherers, social characteristics of an individual based on social status or prestige, such foraging reputation, friendship popularity, and pro-social reputation, can influence the extent to which an individual is embedded in a social network. However, little is known regarding the extent to which height, a physical trait that in Western societies is often associated with social status, is associated in integration in social networks among small-scale hunter gatherers. Here, we investigated the relationship between height and a position an individual occupies in proximity networks among Hadza men (n = 30), hunter-gatherers living in Northern Tanzania. The results of our study show that height is not related to the position an individual maintains in proximity networks. We argue that, in a relatively egalitarian small-scale hunter-gatherer societies such as the Hadza, social interactions driving proximity networks might be influenced by social traits, such as popularity and hunting reputation, rather than physical traits, such as height., (© 2024 The Author(s). American Journal of Human Biology published by Wiley Periodicals LLC.)

Did the COVID-19 pandemic bring people together or push them apart? While infectious diseases tend to push people apart, crises can also bring people together through positive interdependence. We studied this question by asking an international sample (N = 1,006) about their inclinations to cooperate, perceptions of interdependence (i.e., shared fate), and perceived risk as well as local prevalence of COVID-19 infection across 14 time points from March to August, 2020. While perceived interdependence with others tended to increase during this time period, inclinations to cooperate decreased over time. At the within-person level, higher local prevalence of COVID-19 attenuated increases in perceived interdependence with others, and was associated with lower inclinations to cooperate. At the between-person level, people with high perceived interdependence with others reported more stable, or increasing, inclinations to cooperate over time than people with low perceived interdependence. Establishing a high sense of perceived interdependence with others may thus allow people to maintain cooperation during crises, even in the face of challenging circumstances such as those posed by a highly transmissible virus., Competing Interests: We have no conflicts of interest to disclose., (Copyright: © 2024 Guevara Beltran et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

It has been suggested that having a reputation for being prosocial is a critical part of social status across all human societies. It has also been argued that prosocial behavior confers benefits, whether physiological, such as stress reduction, or social, such as building allies or becoming more popular. Here, we investigate the relationship between helping reputation (being named as someone others would go to for help), and hair-derived chronic stress (hair cortisol concentration). In a sample of 77 women and 62 men, we found that perceived helping reputation was not related to chronic stress. Overall, the results of our study suggest that, in an egalitarian society with fluid camp membership and widely practiced generosity such as the Hadza, helping reputation does not necessarily boost stress-related health benefits through prestige-signaling mechanisms observed in hierarchical, large-scale societies., (© 2024. The Author(s).)

Given the importance of friendships during challenging times and the mixed associations between personality traits and disease-related behaviors, we investigated the correlations between personality traits and perceptions of friendships during the COVID-19 pandemic. Data were collected as part of a longitudinal investigation of the correlations between the pandemic and various cooperative relationships. In this investigation, we found that agreeableness and neuroticism predicted participants being more concerned about COVID-19 and bothered by friends' risky behavior, and extraversion predicted enjoying helping friends during the pandemic. Our results suggest that personality differences are associated with how individuals cope with friends' risky behaviors during the COVID-19 pandemic., (© 2023 Elsevier Ltd. All rights reserved.)

In recent years there has been much research regarding the extent to which social status is related to long-term indices of health. The majority of studies looking at the interplay between social status and health have been conducted in industrialized societies. However, it has been argued that most of human evolution took place in small, mobile and egalitarian hunter-gatherer groups where individuals exhibited very little variation in terms of material wealth or possessions. In this study, we looked at the extent to which two domains of social status, hunting reputation (being perceived as a good hunter) and popularity (being perceived as a friend), are related to physiological stress levels among Hadza men, hunter-gatherers living in Northern Tanzania. The results of our study show that neither hunting reputation nor popularity is associated with stress levels. Overall, our data suggest that, in at least some traditional small-scale societies exhibiting an egalitarian social model, such as the Hadza, the variation in social status measures based on both popularity and hunting reputation does not translate into one of the commonly used indices of wellbeing., (© 2023. The Author(s).)

In recent years there has been a great deal of documentation on how social relationships are related to various aspects of human wellbeing. However, until recently most studies investigating the effects of social relationships on wellbeing have applied social network measures to reported social contacts. Recent advances in the application of bio-loggers in biological studies have now made it possible to quantify social relationships based on in-person, rather than self-reported, social interactions. We used GPS-derived in-camp and out-of-camp proximity data to analyse how in-person proximity is related to Hair Cortisol Concentration (HCC) among Hadza hunter-gatherers. Time spent in close proximity to other camp members was associated with higher HCC, especially in women. In contrast, individuals who spent more time in close out-of-camp proximity to their best friend experienced lower HCC. Our study suggests that physiological costs related to group living might be mitigated by in-person interactions with close friends. We also find that the location (i.e., in-camp vs out-of-camp) of proximity to others and self-perceived friends is associated with HCC among the Hadza., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Friendships provide social support and mental health benefits, yet the COVID-19 pandemic has limited interactions with friends. In August 2020, we asked participants ( N  = 634) about their friendships during the pandemic as part of a larger study. We found that younger people and people with higher subjective SES reported more negative effects on their friendships, including feeling more isolated and lonelier. We also found that stress, isolation, and guilt were associated with greater COVID-related social risk-taking, such as making and visiting new friends in person. Our results suggest the pandemic is affecting friendships differently across demographic groups and these negative effects might motivate social risk-taking., (© 2021 Elsevier Ltd. All rights reserved.)

In times of crisis, risk pooling can enhance the resilience of individuals, households and communities. Risk-pooling systems are most effective when their participants adhere to several principles: (1) participants should agree that the pool is for needs that arise unpredictably, not for routine, predictable needs; (2) giving to those in need should not create an obligation for them to repay; (3) participants should not be expected to help others until they have taken care of their own needs; (4) participants should have a consensus about what constitutes need; (5) resources should be either naturally visible or made visible to reduce cheating; (6) individuals should be able to decide which partners to accept; and (7) the scale of the network should be large enough to cover the scale of risks. We discuss the cultural and evolutionary foundations of risk-pooling systems, their vulnerabilities and their relationship to commercial insurance., (© 2021. Springer Nature Limited.)

To better understand risk management and mutual aid among American ranchers, we interviewed and mailed a survey to ranchers in Hidalgo County, New Mexico, and Cochise County, Arizona, focusing on two questions: (1) When do ranchers expect repayment for the help they provide others? (2) What determines ranchers' degrees of involvement in networks of mutual aid, which they refer to as "neighboring"? When needs arise due to unpredictable events, such as injuries, most ranchers reported not expecting to be paid back for the help they provide. When help is provided for something that follows a known schedule or that can be scheduled, such as branding, most ranchers did expect something in return for the help they provide. This pattern makes sense in light of computational modeling that shows that transfers to those in need without expectations of repayment pool risk more effectively than transfers that create debt. Ranchers reported helping other ranchers more often when they belonged to more religious and civic organizations, when they owned larger ranches, when they relied less on ranch vs. other income, and when they had more relatives in the area. Operators of midsize ranches reported helping other ranchers more frequently than did those on smaller and larger ranches. None of our independent variables predicted how many times ranchers reported receiving help from other ranchers. Although ranch culture in the American West is often characterized by an ethic of individualism and independence, our study suggests that this ethic stands alongside an ethic of mutual aid during times of need., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

It is widely believed that there is strong association between physiological stress and an individual's social status in their social hierarchy. This has been claimed for all humans cross-culturally, as well as in non-human animals living in social groups. However, the relationship between stress and social status has not been explored in any egalitarian hunter-gatherer society; it is also under investigated in exclusively female social groups. Most of human evolutionary history was spent in small, mobile foraging bands of hunter-gatherers with little economic differentiation - egalitarian societies. We analysed women's hair cortisol concentration along with two domains of women's social status (foraging reputation and popularity) in an egalitarian hunter-gatherer society, the Hadza. We hypothesized that higher social status would be associated with lower physiological indicators of stress in these women. Surprisingly, we did not find any association between either foraging reputation or popularity and hair cortisol concentration. The results of our study suggest that social status is not a consistent or powerful predictor of physiological stress levels in women in an egalitarian social structure. This challenges the notion that social status has the same basic physiological implications across all demographics and in all human societies., Competing Interests: To protect the anonymity of health data from the Hadza, we will provide a simulated dataset using the R package synthpop (Nowok et al., 2016). This will be available in Figshare at https://figshare.com/s/db1e9606058677b57d2f (DOI: 10.6084/m9.figshare.12789200) from the date of publication., (© The Author(s) 2020.)

According to Turnbull's 1972 ethnography The Mountain People , the Ik of Uganda had a culture of selfishness that made them uncooperative. His claims contrast with two widely accepted principles in evolutionary biology, that humans cooperate on larger scales than other species and that culture is an important facilitator of such cooperation. We use recently collected data to examine Ik culture and its influence on Ik behaviour. Turnbull's observations of selfishness were not necessarily inaccurate but they occurred during a severe famine. Cooperation re-emerged when people once again had enough resources to share. Accordingly, Ik donations in unframed Dictator Games are on par with average donations in Dictator Games played by people around the world. Furthermore, Ik culture includes traits that encourage sharing with those in need and a belief in supernatural punishment of selfishness. When these traits are used to frame Dictator Games, the average amounts given by Ik players increase. Turnbull's claim that the Ik have a culture of selfishness can be rejected. Cooperative norms are resilient, and the consensus among scholars that humans are remarkably cooperative and that human cooperation is supported by culture can remain intact., Competing Interests: The authors declare no competing interests., (© The Author(s) 2020.)

Risk management is a problem humans have faced throughout history and across societies. One way to manage risk is to transfer it to other parties through formal and informal insurance systems. One informal method of self-insurance is limited risk pooling, where individuals can ask for help only when in need. Models suggest that need-based transfer systems may require coordination and common knowledge to be effective. To explore the impact of common knowledge on social coordination and risk pooling in volatile environments, we designed and ran a Risk Pooling Game. We compared participants who played the game with no advance priming or framing to participants who read one of two texts describing real-world systems of risk pooling. Players in the primed games engaged in more repetitive asking and repetitive giving than those in the control games. Players in the primed games also gave more in response to requests and were more likely to respond positively to requests than players in the control games. In addition, players in the primed games were more tolerant of wide differences between what the two players gave and received. These results suggest that the priming texts led players to pay less attention to debt and repayment and more attention to the survival of the other player, and thus to more risk pooling. These results are consistent with findings from fieldwork in small-scale societies that suggest that humans use need-based transfer systems to pool risk when environmental volatility leads to needs with unpredictable timing. Models suggest that the need-based transfer strategy observed in this experiment can outperform debt-based strategies. The results of the present study suggest that the suite of behaviors associated with need-based transfers is an easily triggered part of the human behavioral repertoire., Competing Interests: The authors have declared that no competing interests exist.

Water sharing offers insight into the everyday and, at times, invisible ties that bind people and households with water and to one another. Water sharing can take many forms, including so-called "pure gifts," balanced exchanges, and negative reciprocity. In this paper, we examine water sharing between households as a culturally-embedded practice that may be both need-based and symbolically meaningful. Drawing on a wide-ranging review of diverse literatures, we describe how households practice water sharing cross-culturally in the context of four livelihood strategies (hunter-gatherer, pastoralist, agricultural, and urban). We then explore how cross-cutting material conditions (risks and costs/benefits, infrastructure and technologies), socio-economic processes (social and political power, water entitlements, ethnicity and gender, territorial sovereignty), and cultural norms (moral economies of water, water ontologies, and religious beliefs) shape water sharing practices. Finally, we identify five new directions for future research on water sharing: conceptualization of water sharing; exploitation and status accumulation through water sharing, biocultural approaches to the health risks and benefits of water sharing, cultural meanings and socio-economic values of waters shared; and water sharing as a way to enact resistance and build alternative economies.

Because parental care is expected to depend on the fitness returns generated by each unit of investment, it should be sensitive to both offspring condition and parental ability to invest. The Trivers-Willard Hypothesis (TWH) predicts that parents who are in good condition will bias investment towards sons, while parents who are in poor condition will bias investment towards daughters because high-quality sons are expected to out-reproduce high quality daughters, while low-quality daughters are expected to out-reproduce low quality sons. We report results from an online experiment testing the Trivers-Willard effect by measuring implicit and explicit psychological preferences and behaviorally implied preferences for sons or daughters both as a function of their social and economic status and in the aftermath of a priming task designed to make participants feel wealthy or poor. We find only limited support for predictions derived from the TWH and instead find that women have strong preferences for girls and men have preferences for boys.

Human foragers are obligately group-living, and their high dependence on mutual aid is believed to have characterized our species' social evolution. It was therefore a central adaptive problem for our ancestors to avoid damaging the willingness of other group members to render them assistance. Cognitively, this requires a predictive map of the degree to which others would devalue the individual based on each of various possible acts. With such a map, an individual can avoid socially costly behaviors by anticipating how much audience devaluation a potential action (e.g., stealing) would cause and weigh this against the action's direct payoff (e.g., acquiring). The shame system manifests all of the functional properties required to solve this adaptive problem, with the aversive intensity of shame encoding the social cost. Previous data from three Western(ized) societies indicated that the shame evoked when the individual anticipates committing various acts closely tracks the magnitude of devaluation expressed by audiences in response to those acts. Here we report data supporting the broader claim that shame is a basic part of human biology. We conducted an experiment among 899 participants in 15 small-scale communities scattered around the world. Despite widely varying languages, cultures, and subsistence modes, shame in each community closely tracked the devaluation of local audiences (mean r = +0.84). The fact that the same pattern is encountered in such mutually remote communities suggests that shame's match to audience devaluation is a design feature crafted by selection and not a product of cultural contact or convergent cultural evolution., Competing Interests: The authors declare no conflict of interest.

Fitness interdependence is the degree to which two or more organisms influence each other's success in replicating their genes. Identity fusion may be a proximate mechanism that aligns behavior with fitness interdependence. Although identity fusion may usually lead to behaviors that are fitness enhancing, in evolutionarily novel environments, it may be hijacked in ways that are highly detrimental to fitness.

Problem: The Affordable Care Act charged the Agency for Healthcare Research and Quality to create the Primary Care Extension Program, but did not fund this effort. The idea to work through health extension agents to support health care delivery systems was based on the nationally known Cooperative Extension System (CES). Instead of creating new infrastructure in health care, the CES is an ideal vehicle for increasing health-related research and primary care delivery., Approach: The CES, a long-standing component of the land-grant university system, features a sustained infrastructure for providing education to communities. The Michigan State University (MSU) Model of Health Extension offers another means of developing a National Primary Care Extension Program that is replicable in part because of the presence of the CES throughout the United States. A partnership between the MSU College of Human Medicine and MSU Extension formed in 2014, emphasizing the promotion and support of human health research. The MSU Model of Health Extension includes the following strategies: building partnerships, preparing MSU Extension educators for participation in research, increasing primary care patient referrals and enrollment in health programs, and exploring innovative funding., Outcomes: Since the formation of the MSU Model of Health Extension, researchers and extension professionals have made 200+ connections, and grants have afforded savings in salary costs., Next Steps: The MSU College of Human Medicine and MSU Extension partnership can serve as a model to promote health partnerships nationwide between CES services within land-grant universities and academic health centers or community-based medical schools.

Using an agent-based model to study risk-pooling in herder dyads using rules derived from Maasai osotua ("umbilical cord") relationships, Aktipis et al . (2011) found that osotua transfers led to more risk-pooling and better herd survival than both no transfers and transfers that occurred at frequencies tied to those seen in the osotua simulations. Here we expand this approach by comparing osotua-style transfers to another type of livestock transfer among Maasai known as esile ("debt"). In osotua, one asks if in need, and one gives in response to such requests if doing so will not threaten one's own survival. In esile relationships, accounts are kept and debts must be repaid. We refer to these as "need-based" and "account-keeping" systems, respectively. Need-based transfers lead to more risk pooling and higher survival than account keeping. Need-based transfers also lead to greater wealth equality and are game theoretically dominant to account-keeping rules.

Although the study of signals has been part of human behavioral ecology since the field's inception,(1) only recently has signaling theory become important to the evolutionary study of human behavior and culture.(2) Signaling theory's rise to prominence has been propelled mainly by applications of costly signaling theory,(3) which has shed light on a wide variety of human behaviors ranging from hunting(4) to religion.(5,6) Costly signaling rests on the idea that wasteful but highly visible traits and behaviors can be explained as honest indicators of underlying qualities that are otherwise difficult to detect. For example, a laborious hunting technique may serve as a display of skill on the part of the hunter, who may then be favorably perceived by potential mates and allies.(4) The costs of the activity ensure that the signal is honest, since unskilled hunters will not be able to perform as well. Despite the usefulness of this perspective, many such studies begin by documenting a costly behavior that is then explained with reference to costly signaling theory. Because such behaviors are easy to detect, they may be overemphasized in the literature.(7) Moreover, costly signaling theory by itself can explain neither all signals nor all aspects of signal design. In this review, we argue that a focus on the role that the psychology of the intended receiver plays in signal design can expand the scope of signaling theory as a promising avenue to explain human behavior., (© 2014 Wiley Periodicals, Inc.)

Smaldino argues that evolutionary theories of social behavior do not adequately explain the emergence of group-level traits, including differentiation of roles and organized interactions among individuals. We find Smaldino's account to be commendable but incomplete. Our commentary focuses on a simple question that has not been adequately addressed: What is a group?

The Maasai are a pastoral people in Kenya and Tanzania, whose traditional diet of milk, blood and meat is rich in lactose, fat and cholesterol. In spite of this, they have low levels of blood cholesterol, and seldom suffer from gallstones or cardiac diseases. Field studies in the 1970s suggested that the Maasai have a genetic adaptation for cholesterol homeostasis. Analysis of HapMap 3 data using Fixation Index (Fst) and two metrics of haplotype diversity: the integrated Haplotype Score (iHS) and the Cross Population Extended Haplotype Homozygosity (XP-EHH), identified genomic regions and single nucleotide polymorphisms (SNPs) as strong candidates for recent selection for lactase persistence and cholesterol regulation in 143-156 founder individuals from the Maasai population in Kinyawa, Kenya (MKK). The non-synonmous SNP with the highest genome-wide Fst was the TC polymorphism at rs2241883 in Fatty Acid Binding Protein 1(FABP1), known to reduce low density lipoprotein and tri-glyceride levels in Europeans. The strongest signal identified by all three metrics was a 1.7 Mb region on Chr2q21. This region contains the genes LCT (Lactase) and MCM6 (Minichromosome Maintenance Complex Component) involved in lactase persistence, and the gene Rab3GAP1 (Rab3 GTPase-activating Protein Catalytic Subunit), which contains polymorphisms associated with total cholesterol levels in a genome-wide association study of >100,000 individuals of European ancestry. Sanger sequencing of DNA from six MKK samples showed that the GC-14010 polymorphism in the MCM6 gene, known to be associated with lactase persistence in Africans, is segregating in MKK at high frequency (∼58%). The Cytochrome P450 Family 3 Subfamily A (CYP3A) cluster of genes, involved in cholesterol metabolism, was identified by Fst and iHS as candidate loci under selection. Overall, our study identified several specific genomic regions under selection in the Maasai which contain polymorphisms in genes associated with lactase persistence and cholesterol regulation.

Previous research has shown that the qualities of nuptial gifts among nonhumans and marriage-related property transfers in human societies such as bridewealth and dowry covary with aspects of mate quality. This article explores this issue for another type of marriage-related property transfer: engagement rings. We obtained data on engagement ring costs and other variables through a mail survey sent to recently married individuals living in the American Midwest. This article focuses on survey responses regarding rings that were purchased by men acting alone and using only their own funds who then presented the rings while making surprise proposals of marriage (n = 127). Men marrying younger women spent more on rings, as did men who earned more money and whose fiancées earned more money. These findings suggest that the amounts spent on engagement rings, like bridewealth and dowry payments in other societies, reflect aspects of both male and female mate quality.

This article reviews evolutionary biological studies of sex-biased post-natal parental investment that may be relevant to the issue of preconception gender selection. The focus is on tests of the Trivers-Willard hypothesis, which predicts that natural selection has favoured parents that bias investment in favour of the sex with the best reproductive prospects. Because resource abundance and scarcity often have greater effects on male than on female reproductive success, the Trivers-Willard model predicts that natural selection will most often favour parents who favour males when conditions are good and females when conditions are poor. Empirical tests of this hypothesis are mixed in terms of the appropriateness of their methods and their relevance to the model. Tests with more appropriate measures of such key variables as parental investment tend more often to provide support for the hypothesis. The implications of these findings for the issue of preconception gender selection are briefly discussed.

Dance is believed to be important in the courtship of a variety of species, including humans, but nothing is known about what dance reveals about the underlying phenotypic--or genotypic--quality of the dancer. One measure of quality in evolutionary studies is the degree of bodily symmetry (fluctuating asymmetry, FA), because it measures developmental stability. Does dance quality reveal FA to the observer and is the effect stronger for male dancers than female? To answer these questions, we chose a population that has been measured twice for FA since 1996 (ref. 9) in a society (Jamaican) in which dancing is important in the lives of both sexes. Motion-capture cameras created controlled stimuli (in the form of videos) that isolated dance movements from all other aspects of visual appearance (including FA), and the same population evaluated these videos for dancing ability. Here we report that there are strong positive associations between symmetry and dancing ability, and these associations were stronger in men than in women. In addition, women rate dances by symmetrical men relatively more positively than do men, and more-symmetrical men value symmetry in women dancers more than do less-symmetrical men. In summary, dance in Jamaica seems to show evidence of sexual selection and to reveal important information about the dancer.

The continued exploration of a series of 3-(arylmethyl)-1H-indole-5-carboxamides by the introduction of fluorinated amide substituents has resulted in the discovery of 4-[[5-[((2R)-2-methyl-4,4,4-trifluorobutyl)carbamoyl]-1-methyli ndol- 3-yl]methyl]-3-methoxy-N-[(2-methyl-phenyl)sulfonyl]benzamide (38p, ZENECA ZD3523), which has been chosen for clinical evaluation. This compound exhibited a Ki of 0.42 nM for displacement of [3H]LTD4 on guinea pig lung membranes, a pKB of 10.13 +/- 0.14 versus LTE4 on guinea pig trachea, and an oral ED50 of 1.14 mumol/kg opposite LTD4-induced bronchoconstriction in guinea pigs. The R enantiomer was found to be modestly more potent than the S enantiomer 38o. Modification of the amide substituent to afford achiral compounds was unsuccessful in achieving comparable levels of activity. Profiling of 38p opposite a variety of functional assays has demonstrated the selectivity of this compound as a leukotriene receptor antagonist. The enantioselective synthesis of 38p, which employed a diastereoselective alkylation of (4R,5S)-3-(1-oxo-4,4,4-trifluorobutyl)-4-methyl-5-phenyl-2-oxazoli dinone (27) as the key step to establish the chirality of the amide substituent, provided an efficient route for generating 38p in > 99% enantiomeric purity.

Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl] methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]- 3- methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a transposed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.

1,6-Substituted and 3,5-substituted indoles and indazoles containing acylamino and N-arylsulfonyl amide appendages are potent antagonists of the peptidoleukotrienes LTD4 and LTE4. A compound from the 3,5-substituted indole series, N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]-1-methylindol- 3-yl]methyl]-3-methoxybenzoyl]-2-methyl-benzenesulfonamide (ICI 204,219), is undergoing clinical evaluation for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude; N-[4-[[6-(cyclopentylacetamido)-3-[2-(N- methylcarbamoyl)ethyl]indol-1-yl]methyl]-3-methoxy- benzoyl]benzenesulfonamide (15c) has a pKB of 10.7 at the LTD4 receptor on guinea pig trachea. Modifications of the acylamino portion of the disubstituted antagonists demonstrated that a transposition of the amide CO and NH atoms was viable. N-Cyclopentylmethyl amides in both the 1,6- and 3,5-disubstituted indole series were 1 order of magnitude less potent than the corresponding cyclopentylacetamides. In both series this potency loss could be regained by the incorporation of a propionamide substituent at either C-3 or N-1, respectively. For example, N-[4-[[6-[N-(cyclopentylmethyl)carbamoyl]-3-[2-(pyrrolidin-1 - methylbenzenesulfonamide (39c) has a pKB of 9.5.

Female-biased parental investment is unusual but not unknown in human societies. Relevant explanatory models include Fisher's principle, the Trivers-Willard model, local mate and resource competition and enhancement, and economic rational actor models. Possible evidence of female-biased parental investment includes sex ratios, mortality rates, parents' stated preferences for offspring of one sex, and direct and indirect measurements of actual parental behavior. Possible examples of female-biased parental investment include the Mukogodo of Kenya, the Ifalukese of Micronesia, the Cheyenne of North America, the Herero of southern Africa, the Kanjar of south Asia, the Mundugumor of New Guinea, contemporary North America, and historical Germany, Portugal, and the United States.

The dissociation constants (KB) at the LTD4 receptor on guinea pig trachea of a series of monocyclic and bicyclic cyclopentylurethane and cyclopentylacetamide N-arylsulfonyl amides have been measured. The KB was found to be remarkably tolerant of changes in the electronic constitution and lipophilicity of the bicyclic ring system (template). Thus, N-[4[[6-[[(cyclopentyloxy)carbonyl]amino]benzimidazol-1- yl]methyl]-3-methoxybenzoyl]benzenesulfonamide (11a) and N-[4-[[5-[[(cyclopentyloxy)carbonyl]amino]benzo[b]thien-3- yl]methyl]-3-methoxybenzoyl]benzene-sulfonamide (25a) had closely similar affinities (pKB, 9.20 and 9.31, respectively; LTE4 as agonist). It has been shown that the hetero-ring of the template need not be aromatic in order to achieve high affinity, since indoline 31 and 2,3-dihydrobenz-1,4-oxazines 37a-c had pKBs greater than 9. Further, it has been shown that an o-aminophenone (see 42 and Figure 3) can function as a template; the template in 42 [see iii] is bicyclic by virtue of the presence of an intramolecular hydrogen bond. In contrast, when the template is a phenyl ring (48), receptor affinity is markedly reduced. These findings support the notion that central bicyclic ring system in this family of peptidoleukotriene antagonists is a molecular feature which helps to preorganize the acylamino and acidic chains and thereby facilitate the molecular recognition event.

A systematic structure-activity exploration of the carboxylic acid region in a series of indole- or indazole-derived leukotriene antagonists 1 led to several discoveries. Use of the 3-methoxy-p-tolyl fragment (illustrated in acid 1) for connecting the indole and the acidic site provides the most potent carboxylic acids 1, tetrazoles 20, and aryl sulfonimides 21. The aryl sulfonimides are 5-500 times more potent (in vitro and/or in vivo) than the corresponding carboxylic acids 1. The o-tolyl sulfonimides such as 114 show greater oral potency than the phenyl sulfonimides at a given level of in vitro activity. Acidic keto sulfone derivatives 10 (Nu = CH-(CO2CH3)SO2Ph) mimic the activity of the sulfonimides.

A perception of structural similarities between two independent series of leukotriene antagonists (one emanating from FPL 55712 and one based upon the leukotrienes themselves) led to the discovery of a novel class of indole and indazole derived antagonists of peptidoleukotrienes. A systematic exploration of C-6 substituted 4-(indol-1-ylmethyl)-3-methoxybenzoic acids identified cyclopentylacetamide and cyclopentylurethane as preferred substituents. The corresponding indazoles were equipotent. These compounds are selective leukotriene antagonists with pKB values of 7.5-7.8 vs LTE4 on guinea pig trachea.